4-Amino-2,3-disubstituted thieno[2,3-d]pyrimidines and pharmacetical compositions thereof

ABSTRACT

Furo- and thienopyrimidine derivatives, which are useful as TIE-2 and/or VEGFR-2 inhibitors are described herein. The described invention also includes methods of making such furo- and thienopyrimidine derivatives as well as methods of using the same in the treatment of hyperproliferative diseases.

This This application is filed pursuant to 35 U.S.C. § 371 as a UnitedStates National Phase Application of International Application No.PCT/US02/28650 filed Sep. 10, 2002, which claims priority from US60/318,766 filed Sep. 11, 2001.

BACKGROUND OF THE INVENTION

The present invention relates to furo- and thienopyrimidine derivatives,compositions and medicaments containing the same, as well as processesfor the preparation and use of such compounds, compositions andmedicaments. Such furo- and thienopyrimidine derivatives are useful inthe treatment of diseases associated with inappropriate angiogenesis.

The process of angiogenesis is the development of new blood vessels,generally capillaries, from pre-existing vasculature. Angiogenesis isdefined as involving (i) activation of endothelial cells; (ii) increasedvascular permeability; (iii) subsequent dissolution of the basementmembrane and extravisation of plasma components leading to formation ofa provisional fibrin gel extracellular matrix; (iv) proliferation andmobilization of endothelial cells; (v) reorganization of mobilizedendothelial cells to form functional capillaries; (vi) capillary loopformation; and (vii) deposition of basement membrane and recruitment ofperivascular cells to newly formed vessels. Normal angiogenesis isactivated during tissue growth, from embryonic development throughmaturity, and then enters a period of relative quiescence duringadulthood. Normal angiogensesis is also activated during wound healing,and at certain stages of the female reproductive cycle. Inappropriateangiogenesis has been associated with several disease states includingvarious retinopathies; ischemic disease; atherosclerosis; chronicinflammatory disorders; and cancer. The role of angiogenesis in diseasestates is discussed, for instance, in Fan et al, Trends in PharmacolSci. 16:54–66; Shawver et al, DDT Vol. 2, No. 2 February 1997; Folkmann,1995, Nature Medicine 1:27–31.

In cancer the growth of solid tumors has been shown to be angiogenesisdependent. (See Folkmann, J., J. Nat'l. Cancer Inst., 1990, 82, 4–6.)Consequently, the targeting of pro-angiogenic pathways is a strategybeing widely pursued in order to provide new therapeutics in these areasof great, unmet medical need. The role of tyrosine kinases involved inangiogenesis and in the vascularization of solid tumors has drawninterest. Until recently most interest in this area has focused ongrowth factors such as vascular endothelial growth factor (VEGF) and itsreceptors termed vascular endothelial growth factor receptor(s) (VEGFR).VEGF, a polypeptide, is mitogenic for endothelial cells in vitro andstimulates angiogenic responses in vivo. VEGF has also been linked toinappropriate angiogenesis (Pinedo, H. M. et al The Oncologist, Vol. 5,No. 90001, 1–2, April 2000). VEGFR(s) are protein tyrosine kinases(PTKs). PTKs catalyze the phosphorylation of specific tyrosyl residuesin proteins involved in the regulation of cell growth anddifferentiation. (A. F. Wilks, Progress in Growth Factor Research, 1990,2, 97–111; S. A. Courtneidge, Dev. Supp.l, 1993, 57–64; J. A. Cooper,Semin. Cell Biol., 1994, 5(6), 377–387; R. F. Paulson, Semin. Immunol.,1995, 7(4), 267–277; A. C. Chan, Curr. Opin. Immunol., 1996, 8(3),394–401).

Three PTK receptors for VEGF have been identified: VEGFR-1 (Flt-1);VEGFR-2 (Flk-1 or KDR) and VEGFR-3 (Flt-4). These receptors are involvedin angiogenesis and participate in signal transduction (Mustonen, T. etal J. Cell Biol. 1995:129:895–898). Of particular interest is VEGFR-2,which is a transmembrane receptor PTK expressed primarily in endothelialcells. Activation of VEGFR-2 by VEGF is a critical step in the signaltransduction pathway that initiates tumor angiogenesis. VEGF expressionmay be constitutive to tumor cells and can also be upregulated inresponse to certain stimuli. One such stimuli is hypoxia, where VEGFexpression is upregulated in both tumor and associated host tissues. TheVEGF ligand activates VEGFR-2 by binding with its extracellular VEGFbinding site. This leads to receptor dimerization of VEGFRs andautophosphorylation of tyrosine residues at the intracellular kinasedomain of VEGFR-2. The kinase domain operates to transfer a phosphatefrom ATP to the tyrosine residues, thus providing binding sites forsignaling proteins downstream of VEGFR-2 leading ultimately toinitiation of angiogenesis (McMahon, G., The Oncologist, Vol. 5, No.90001, 3–10, April 2000).

Angiopoieten 1 (Ang1), a ligand for the endothelium-specific receptortyrosine kinase TIE-2 is a novel angiogenic factor (Davis et al, Cell,1996, 87:1161–1169; Partanen et al, Mol. Cell Biol, 12:1698–1707 (1992);U.S. Pat. Nos. 5,521,073; 5,879,672; 5,877,020; and 6,030,831). Theacronym TIE represents “tyrosine kinase containing Ig and EGF homologydomains”. TIE is used to identify a class of receptor tyrosine kinases,which are exclusively expressed in vascular endothelial cells and earlyhemopoietic cells. Typically, TIE receptor kinases are characterized bythe presence of an EGF-like domain and an immunoglobulin (IG) likedomain, which consists of extracellular folding units, stabilized byintra-chain disulfide bonds (Partanen et al Curr. Topics Microbiol.Immunol., 1999, 237:159–172). Unlike VEGF, which functions during theearly stages of vascular development, Ang1 and its receptor TIE-2function in the later stages of vascular development, i.e., duringvascular remodeling (remodeling refers to formation of a vascular lumen)and maturation (Yancopoulos et al, Cell, 1998, 93:661–664; Peters, K.G., Circ. Res., 1998, 83(3):342–3; Suri et al, Cell 87, 1171–1180(1996)).

Consequently, inhibition of TIE-2 would be expected to serve to disruptremodeling and maturation of new vasculature initiated by angiogenesisthereby disrupting the angiogenic process. Furthermore, inhibition atthe kinase domain binding site of VEGFR-2 would block phosphorylation oftyrosine residues and serve to disrupt initiation of angiogenesis.Presumably then, inhibition of TIE-2 and/or VEGFR-2 should prevent tumorangiogenesis and serve to retard or eradicate tumor growth. Accordingly,a treatment for cancer or other disorder associated with inappropriateangiogenesis could be provided.

The present inventors have discovered novel furo- and thienopyrimidinecompounds, which are inhibitors of TIE-2 and/or VEGFR-2 kinase activity.Such furo- and thienopyrimidine derivatives are useful in the treatmentof disorders, including cancer, associated with inappropriateangiogenesis.

BRIEF SUMMARY OF THE INVENTION

In one aspect of the present invention, there is provided a compound ofFormula (I):

or a salt, solvate, or physiologically functional derivative thereof:wherein:

-   X is O or S;-   A is hydrogen, halo, C₁–C₆ alkyl, aryl, heteroaryl, aryl or    heteroaryl substituted with at least one independently selected R³    group, heterocyclyl, —RR³, —C(O)OR⁴, —C(O)NR⁵R⁶, or —C(O)R⁴;-   D is hydrogen, halo, C₁–C₆ alkyl, aryl, heteroaryl, aryl or    heteroaryl substituted with at least one independently selected R³    group, heterocyclyl, —RR³, —C(O)O R⁴, —C(O)NR⁵R⁶, or —C(O)R⁴;-   R is C₁–C₆ alkylene, C₃–C₇ cycloalkylene, C₁–C₆ alkenylene, or C₁–C₆    alkynylene;-   R¹ is hydrogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, —SR⁴, —S(O)₂R⁴, —NR⁷, R⁷,    —NR′NR′″R″″, —N(H)RR³, —C(O)OR⁷, or —C(O)NR⁷R⁷;-   R² is hydrogen, —OH, —NR⁷R⁷ or ═NH;-   R³ is halo, C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₃–C₇    cycloalkoxy, C₁–C₆ haloalkoxy, aryl, aralkyl, aryloxy, heteroaryl,    heterocyclyl, —CN, —NHC(O)R⁴, —N(R⁸)HC(O)R⁴, —NHC(S)R⁴, —NR⁵R⁶, —RN    R⁵R⁶, —SR⁴, —S(O)₂R⁴, —RC(O)OR⁴, —C(O)OR⁴, —C(O)R⁴, —C(O)NR⁵R⁶,    —NHS(O)₂R⁴, —N(S(O)₂R⁴)S(O)₂R⁴, —S(O)₂NR⁵R⁶, or —NHC(═NH)R⁴;-   R⁴ is hydrogen, C₁–C₆ alkyl, aryl, heteroaryl, heterocyclyl, —RR³,    —NR′″R″″, or —NR′NR′″R″″;-   R⁵ is hydrogen, C₁–C₆ alkyl, C₃–C₇ cycloalkyl, cyanoalkyl, —R′R″,    aryl, aralkyl, heteroaryl, —NHC(O)OR′″, —R′NHC(O)OR′″,    —R′NHC(O)NR′″R″″, or —R′C(O)OR′″;-   R⁶ is hydrogen, C₁–C₆ alkyl, C₃–C₇ cycloalkyl, cyanoalkyl, —R′R″,    aryl, aralkyl, heteroaryl, —C(O)OR′″, or —R′C(O)NR′″R′″;-   R⁷ is hydrogen, C₁–C₆ alkyl, aryl, or —C(O)OR′″;-   R⁸ is C₁–C₃ alkyl;-   R′ is C₁–C₃ alkylene;-   R″ is heteroalkyl or NR′″R″″;-   R′″ is hydrogen, C₁–C₆ alkyl, aryl, aralkyl, heteroaryl, or C₃–C₇    cycloalkyl;-   R″″ is hydrogen, C₁–C₆ alkyl, aryl, heteroaryl, or C₃–C₇ cycloalkyl.

In a second aspect of the present invention, there is provided acompound of Formula (II):

or a salt, solvate, or physiologically functional derivative thereof:wherein:

-   A is hydrogen, halo, C₁–C₆ alkyl, aryl, heteroaryl, aryl or    heteroaryl substituted with at least one independently selected R³    group, heterocyclyl, —RR³, —C(O)OR⁴, —C(O)NR⁵R⁶, or —C(O)R⁴;-   D is hydrogen, halo, C₁–C₆ alkyl, aryl, heteroaryl, aryl or    heteroaryl substituted with at least one independently selected R³    group, heterocyclyl, —RR³, —C(O)OR⁴, —C(O)NR⁵R⁶, or —C(O)R⁴;-   R is C₁–C₆ alkylene, C₃–C₇ cycloalkylene, C₁–C₆ alkenylene, or C₁–C₆    alkynylene;-   R³ is halo, C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₃–C₇    cycloalkoxy, C₁–C₆ haloalkoxy, aryl, aralkyl, aryloxy, heteroaryl,    heterocyclyl, —CN, —NHC(O)R⁴, —N(R⁸)HC(O)R⁴, —NHC(S)R⁴, —NR⁵R⁶, —RN    R⁵R⁶, —SR⁴, —S(O)₂R⁴, —RC(O)OR⁴, —C(O)OR⁴, C(O)R⁴, —C(O)NR⁵R⁶,    —NHS(O)₂R⁴, —N(S(O)₂R⁴)S(O)₂R⁴, —S(O)₂NR⁵R⁶, or —NHC(═NH)R⁴;-   R⁴ is hydrogen, C₁–C₆ alkyl, aryl, heteroaryl, heterocyclyl, —RR³,    —NR′″R″″, or —NR′NR′″R″″;-   R⁵ is hydrogen, C₁–C₆ alkyl, C₃–C₇ cycloalkyl, cyanoalkyl, —R′R″,    aryl, aralkyl, heteroaryl, —NHC(O)OR′″, —R′NHC(O)OR′″,    —R′NHC(O)NR′″R″″, or —R′C(O)OR′″;-   R⁶ is hydrogen, C₁–C₆ alkyl, C₃–C₇ cycloalkyl, cyanoalkyl, —R′R″,    aryl, aralkyl, heteroaryl, —C(O)OR′″, or —R′C(O)NR′″R′″;-   R⁸ is C₁–C₃ alkyl;-   R′ is C₁–C₃ alkylene;-   R″ is heteroalkyl or NR′″R″″;-   R′″ is hydrogen, C₁–C₆ alkyl, aryl, aralkyl, heteroaryl, or C₃–C₇    cycloalkyl;-   R″″ is hydrogen, C₁–C₆ alkyl, aryl, heteroaryl, or C₃–C₇ cycloalkyl.

In a third aspect of the present invention, there is provided a compoundof Formula (III):

or a salt, solvate, or physiologically functional derivative thereof:wherein:

-   A is hydrogen, halo, C₁–C₆ alkyl, aryl, heteroaryl, aryl or    heteroaryl substituted with at least one independently selected R³    group, heterocyclyl, —RR³, —C(O)OR⁴, —C(O)NR⁵R⁶, or —C(O)R⁴;-   D is hydrogen, halo, C₁–C₆ alkyl, aryl, heteroaryl, aryl or    heteroaryl substituted with at least one independently selected R³    group, heterocyclyl, —RR³, —C(O)OR⁴, —C(O)NR⁵R⁶, or —C(O)R⁴;-   R is C₁–C₆ alkylene, C₃–C₇ cycloalkylene, C₁–C₆ alkenylene, or C₁–C₆    alkynylene;-   R³ is halo, C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₃–C₇    cycloalkoxy, C₁–C₆ haloalkoxy, aryl, aralkyl, aryloxy, heteroaryl,    heterocyclyl, —CN, —NHC(O)R⁴, —N(R⁸)HC(O)R⁴, —NHC(S)R⁴, —N R⁵R⁶, —RN    R⁵R⁶, —SR⁴, —S(O)₂R⁴, —RC(O)OR⁴, —C(O)OR⁴, C(O)R⁴, —C(O)NR⁵R⁶,    —NHS(O)₂R⁴, —N(S(O)₂R⁴)S(O)₂R⁴, —S(O)₂NR⁵R⁶, or —NHC(═NH)R⁴;-   R⁴ is hydrogen, C₁–C₆ alkyl, aryl, heteroaryl, heterocyclyl, —RR³,    —NR′″R″″, or —NR′NR′″R″″;-   R⁵ is hydrogen, C₁–C₆ alkyl, C₃–C₇ cycloalkyl, cyanoalkyl, —R′R″,    aryl, aralkyl, heteroaryl, —NHC(O)OR′″, —R′NHC(O)OR′″,    —R′NHC(O)NR′″R″″, or —R′C(O)OR′″;-   R⁶ is hydrogen, C₁–C₆ alkyl, C₃–C₇ cycloalkyl, cyanoalkyl, —R′R″,    aryl, aralkyl, heteroaryl, —C(O)OR′″, or —R′C(O)NR′″R′″;-   R⁸ is C₁–C₃ alkyl;-   R′ is C₁–C₃ alkylene;-   R″ is heteroalkyl or NR′″R″″;-   R′″ is hydrogen, C₁–C₆ alkyl, aryl, aralkyl, heteroaryl, or C₃–C₇    cycloalkyl;-   R″″ is hydrogen, C₁–C₆ alkyl, aryl, heteroaryl, or C₃–C₇ cycloalkyl.

In a fourth aspect of the present invention, there is provided acompound of formula (II):

or a salt, solvate, or physiologically functional derivative thereof:wherein:

-   A is halo, C₁–C₆ alkyl, aryl, heteroaryl, aryl or heteroaryl    substituted with at least one independently selected R³ group,    heterocyclyl, —RR³, —C(O)OR⁴, —C(O)NR⁵R⁶, or —C(O)R⁴;-   D is halo, C₁–C₆ alkyl, aryl, heteroaryl, aryl or heteroaryl    substituted with at least one independently selected R³ group,    heterocyclyl, —RR³, —C(O)OR⁴, —C(O)NR⁵R⁶, or —C(O)R⁴;-   R is C₁–C₆ alkylene, C₁–C₆ alkenylene, or C₁–C₆ alkynylene;-   R³ is halo, C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₃–C₇    cycloalkoxy, C₁–C₆ haloalkoxy, aryl, aralkyl, aryloxy, heteroaryl,    heterocyclyl, —CN, —NHC(O)R⁴, —N(R⁸)HC(O)R⁴, —NHC(S)R⁴, —N R⁵R⁶, —RN    R⁵R⁶, —SR⁴, —S(O)₂R⁴, —RC(O)OR⁴, —C(O)OR⁴, C(O)R⁴, —C(O)NR⁵R⁶,    —NHS(O)₂R⁴, —N(S(O)₂R⁴)S(O)₂R⁴, —S(O)₂NR⁵R⁶, or —NHC(═NH)R⁴;-   R⁴ is hydrogen, C₁–C₆ alkyl, aryl, heteroaryl, heterocyclyl, —RR³,    —NR′″R″″, or —NR′NR′″R″″;-   R⁵ is hydrogen, C₁–C₆ alkyl, C₃–C₇ cycloalkyl, cyanoalkyl, —R′ R″,    aryl, aralkyl, heteroaryl, —NHC(O)OR′″, —R′NHC(O)OR′″,    —R′NHC(O)NR′″R″″, or —R′C(O)OR′″;-   R⁶ is hydrogen, C₁–C₆ alkyl, C₃–C₇ cycloalkyl, cyanoalkyl, —R′R″,    aryl, aralkyl, heteroaryl, —C(O)OR′″, or —R′C(O)NR′″R′″;-   R⁸ is C₁–C₃ alkyl;-   R′ is C₁–C₃ alkylene;-   R″ is heteroalkyl or NR′″R″″;-   R′″ is hydrogen, C₁–C₆ alkyl, aryl, aralkyl, heteroaryl, or C₃–C₇    cycloalkyl;-   R″″ is hydrogen, C₁–C₆ alkyl, aryl, heteroaryl, or C₃–C₇ cycloalkyl.

In a fifth aspect of the present invention, there is provided a compoundof Formula (II):

or a salt, solvate, or physiologically functional derivative thereof:wherein:

-   A is halo, C₁–C₆ alkyl, aryl, heteroaryl, aryl or heteroaryl    substituted with at least one independently selected R³ group,    heterocyclyl, —RR³, —C(O)OR⁴, —C(O)NR⁵R⁶, or —C(O)R⁴;-   D is hydrogen or halo;-   R is C₁–C₆ alkylene, C₃–C₇ cycloalkylene, C₁–C₆ alkenylene, or C₁–C₆    alkynylene;-   R³ is halo, C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₃–C₇    cycloalkoxy, C₁–C₆ haloalkoxy, aralkyl, aryloxy, heterocyclyl, —CN,    —NHC(O)R⁴, —N(R⁸)HC(O)R⁴, —NHC(S)R⁴, —NR⁵R⁶, —R NR⁵R⁶, —SR⁴,    —S(O)₂R⁴, —RC(O)OR⁴, —C(O)OR⁴, C(O)R⁴, —C(O)NR⁵R⁶, —NHS(O)₂R⁴,    —N(S(O)₂R⁴)S(O)₂R⁴, —S(O)₂NR⁵R⁶, or —NHC(═NH)R⁴;-   R⁴ is hydrogen, C₁–C₆ alkyl, aryl, heteroaryl, heterocyclyl, —RR³,    —NR′″R″″, or —NR′NR′″R″″;-   R⁵ is hydrogen, C₁–C₆ alkyl, C₃–C₇ cycloalkyl, cyanoalkyl, —R′ R″,    aryl, aralkyl, heteroaryl, —NHC(O)OR′″, —R′NHC(O)OR′″,    —R′NHC(O)NR′″R″″, or —R′C(O)OR′″;-   R⁶ is hydrogen, C₁–C₆ alkyl, C₃–C₇ cycloalkyl, cyanoalkyl, —R′R″,    aryl, aralkyl, heteroaryl, —C(O)OR′″, or —R′C(O)NR′″R′″;-   R⁸ is C₁–C₃ alkyl;-   R′ is C₁–C₃ alkylene;-   R″ is heteroalkyl or NR′″R″″;-   R′″ is hydrogen, C₁–C₆ alkyl, aryl, aralkyl, heteroaryl, or C₃–C₇    cycloalkyl;-   R″″ is hydrogen, C₁–C₆ alkyl, aryl, heteroaryl, or C₃–C₇ cycloalkyl.

In a sixth aspect of the present invention, there is provided a compoundof Formula (III):

or a salt, solvate, or physiologically functional derivative thereof:wherein:

-   A is halo, C₁–C₆ alkyl, aryl, heteroaryl, aryl or heteroaryl    substituted with at least one independently selected R³ group,    heterocyclyl, —RR³, —C(O)OR⁴, —C(O)NR⁵R⁶, or —C(O)R⁴;-   D is hydrogen or halo;-   R is C₁–C₆ alkylene, C₃–C₇ cycloalkylene, C₁–C₆ alkenylene, or C₁–C₆    alkynylene;-   R³ is halo, C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₃–C₇    cycloalkoxy, C₁–C₆ haloalkoxy, aralkyl, aryloxy, heterocyclyl, —CN,    —NHC(O)R⁴, —N(R⁸)HC(O)R⁴, —NHC(S)R⁴, —NR⁵R⁶, —R NR⁵R⁶, —SR⁴,    —S(O)₂R⁴, —RC(O)OR⁴, —C(O)OR⁴, C(O)R⁴, —C(O)NR⁵R⁶, —NHS(O)₂R⁴,    —N(S(O)₂R⁴)S(O)₂R⁴, —S(O)₂NR⁵R⁶, or —NHC(═NH)R⁴;-   R⁴ is hydrogen, C₁–C₆ alkyl, aryl, heteroaryl, heterocyclyl, —RR³,    —NR′″R″″, or —NR′NR′″R″″;-   R⁵ is hydrogen, C₁–C₆ alkyl, C₃–C₇ cycloalkyl, cyanoalkyl, —R′ R″,    aryl, aralkyl, heteroaryl, —NHC(O)OR′″, —R′NHC(O)OR′″,    —R′NHC(O)NR′″R″″, or —R′C(O)OR′″;

R⁶ is hydrogen, C₁–C₆ alkyl, C₃–C₇ cycloalkyl, cyanoalkyl, —R′R″, aryl,aralkyl, heteroaryl, —C(O)OR′″, or —R′C(O)NR′″R′″;

-   R⁸ is C₁–C₃ alkyl;-   R′ is C₁–C₃ alkylene;-   R″ is heteroalkyl or NR′″R″″;-   R′″ is hydrogen, C₁–C₆ alkyl, aryl, aralkyl, heteroaryl, or C₃–C₇    cycloalkyl;-   R″″ is hydrogen, C₁–C₆ alkyl, aryl, heteroaryl, or C₃–C₇ cycloalkyl.

In a seventh aspect of the present invention, there is provided acompound of Formula (IV):

or a salt, solvate, or physiologically functional derivative thereof:wherein:

-   X is O or S;-   D is hydrogen, halo, C₁–C₆ alkyl, aryl, heteroaryl, aryl or    heteroaryl substituted with at least one independently selected R³    group, heterocyclyl, —RR³, —C(O)O R⁴, —C(O)NR⁵R⁶, or —C(O)R⁴;-   R is C₁–C₆ alkylene, C₃–C₇ cycloalkylene, C₁–C₆ alkenylene, or C₁–C₆    alkynylene;-   R¹ is hydrogen, C₁–C₆ alkyl, C₁–C₆ alkoxy, —SR⁴, —S(O)₂R⁴, —NR⁷R⁷,    —NR′NR′″R″″, —N(H)RR³, —C(O)OR⁷, or —C(O)NR⁷R⁷;-   R² is hydrogen, —OH, —NR⁷R⁷ or ═NH;-   R³ is halo, C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₃–C₇    cycloalkoxy, C₁–C₆ haloalkoxy, aryl, aralkyl, aryloxy, heteroaryl,    heterocyclyl, —CN, —NHC(O)R⁴, —N(R⁸)HC(O)R⁴, —NHC(S)R⁴, —NR⁵R⁶, —RN    R⁵R⁶, —SR⁴, —S(O)₂R⁴, —RC(O)OR⁴, —C(O)OR⁴, —C(O)R⁴, —C(O)NR⁵R⁶,    —NHS(O)₂R⁴, —N(S(O)₂R⁴)S(O)₂R⁴, —S(O)₂NR⁵R⁶, or —NHC(═NH)R⁴;-   R^(3a) is —NHC(O) R⁴, —N(R⁸)HC(O) R⁴, —NHC(S) R⁴, —NR⁵R⁶, —RN R⁵R⁶,    —C(O)NR⁵R⁶, —NHS(O)₂R⁴, —N(S(O)₂R⁴)S(O)₂R⁴, —S(O)₂NR⁵R⁶, or    —NHC(═NH)R⁴;-   R⁴ is hydrogen, C₁–C₆ alkyl, aryl, heteroaryl, heterocyclyl, —RR³,    —NR′″R″″, or —NR′NR′″R″″;-   R⁵ is hydrogen, C₁–C₆ alkyl, C₃–C₇ cycloalkyl, cyanoalkyl, —R′R″,    aryl, aralkyl, heteroaryl, —NHC(O)OR′″, —R′NHC(O)OR′″,    —R′NHC(O)NR′″R″″, or —R′C(O)OR′″;-   R⁶ is hydrogen, C₁–C₆ alkyl, C₃–C₇ cycloalkyl, cyanoalkyl, —R′R″,    aryl, aralkyl, heteroaryl, —C(O)OR′″, or —R′C(O)NR′″R′″;-   R⁷ is hydrogen, C₁–C₆ alkyl, aryl, or —C(O)OR′″;-   R⁸ is C₁–C₃ alkyl;-   R′ is C₁–C₃ alkylene;-   R″ is heteroalkyl or NR′″R″″;-   R′″ is hydrogen, C₁–C₆ alkyl, aryl, aralkyl, heteroaryl, or C₃–C₇    cycloalkyl;-   R″″ is hydrogen, C₁–C₆ alkyl, aryl, heteroaryl, or C₃–C₇ cycloalkyl.

In an eighth aspect of the present invention, there is provided apharmaceutical composition comprising a therapeutically effective amountof a compound of formula (I), or a salt, solvate, or a physiologicallyfunctional derivative thereof and one or more of pharmaceuticallyacceptable carriers, diluents and excipients.

In a ninth aspect of the present invention, there is provided a methodof treating a disorder in a mammal, said disorder being mediated by atleast one of inappropriate TIE-2 and VEGFR-2 activity, comprising:administering to said mammal a therapeutically effective amount of acompound of formula (I) or a salt, solvate or a physiologicallyfunctional derivative thereof.

In a tenth aspect of the present invention, there is provided a compoundof formula (I), or a salt, solvate, or a physiologically functionalderivative thereof for use in therapy.

In an eleventh aspect of the present invention, there is provided theuse of a compound of formula (I), or a salt, solvate, or aphysiologically functional derivative thereof in the preparation of amedicament for use in the treatment of a disorder mediated by at leastone of inappropriate TIE-2 and VEGFR-2 activity.

In a twelvth aspect of the present invention, there is provided a methodof treating a disorder in a mammal, said disorder being mediated by atleast one of inappropriate TIE-2 and VEGFR-2 activity, comprising:administering to said mammal therapeutically effective amounts of (i) acompound of formula (I), or a salt, solvate or physiologicallyfunctional derivative thereof and (ii) an agent to inhibit growth factorreceptor function.

In a thirteenth aspect of the present invention, there is provided amethod of treating a disorder in a mammal, said disorder beingcharacterized by inappropriate angiogenesis, comprising: administeringto said mammal a therapeutically effective amount of a compound offormula (I), or a salt, solvate or physiologically functional derivativethereof.

DETAILED DESCRIPTION

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder. The term also includes within its scope amountseffective to enhance normal physiological function.

As used herein, the numbering of the furo[2,3-d]pyrimidine scaffold informula (I) is assigned as shown in the structure following.

As used herein, the term “alkyl” refers to a straight or branched chainhydrocarbon radical having from one to twelve carbon atoms, optionallysubstituted with substituents selected from the group consisting ofC₁–C₆ alkyl, C₁–C₆ hydroxyalkyl, C₁–C₆ alkoxy, C₁–C₆ alkylsulfanyl,C₁–C₆ alkylsulfenyl, C₁–C₆ alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aryl, aryloxy, heteroaryl, aminosulfonyloptionally substituted by alkyl, nitro, cyano, halogen, or C₁–C₆perfluoroalkyl, multiple degrees of substitution being allowed. Examplesof “alkyl” as used herein include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl,isopentyl, and the like.

As used herein, the term “C₁–C₆ alkyl” refers to an alkyl group asdefined above containing at least 1, and at most 6, carbon atoms.Examples of branched or straight chained “C₁–C₆ alkyl” groups useful inthe present invention include, but are not limited to, methyl, ethyl,n-propyl, isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl, andisopentyl.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical having from one to ten carbon atoms,optionally substituted with substituents selected from the group whichincludes C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆alkylsulfenyl, C₁–C₆ alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen and C₁–C₆ perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “alkylene” as used hereininclude, but are not limited to, methylene, ethylene, n-propylene,n-butylene, and the like.

As used herein, the term “C₁–C₃ alkylene” refers to an alkylene group,as defined above, which contains at least 1, and at most 3, carbon atomsrespectively. Examples of “C₁–C₃ alkylene” groups useful in the presentinvention include, but are not limited to, methylene, ethylene, andn-propylene.

As used herein, the term “alkenyl” refers to a hydrocarbon radicalhaving from two to ten carbons and at least one carbon-carbon doublebond, optionally substituted with substituents selected from the groupwhich includes C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆alkylsulfenyl, C₁–C₆ alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen and C₁–C₆ perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “alkenyl” as used hereininclude, ethenyl, propenyl, 1-butenyl, 2-butenyl, and isobutenyl.

As used herein, the term “C₁–C₆ alkenyl” refers to an alkenyl group asdefined above containing at least 1, and at most 6, carbon atoms.Examples of “C₁–C₆ alkyl” groups useful in the present inventioninclude, but are not limited to, ethenyl, propenyl, 1-butenyl,2-butenyl, and isobutenyl.

As used herein, the term “alkenylene” refers to an straight or branchedchain divalent hydrocarbon radical having from two to ten carbon atomsand one or more carbon—carbon double bonds, optionally substituted withsubstituents selected from the group which includes C₁–C₆ alkyl, C₁–C₆alkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆ alkylsulfenyl, C₁–C₆ alkylsulfonyl,oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, nitro, cyano, halogen and C₁–C₆ perfluoroalkyl,multiple degrees of substitution being allowed. Examples of “alkenylene”as used herein include, but are not limited to, ethene-1,2-diyl,propene-1,3-diyl, methylene-1,1-diyl, and the like.

As used herein, the term “C₁–C₃ alkenylene” refers to an alkenylenegroup as defined above containing at least 1, and at most 3, carbonatoms. Examples of “C₁–C₃ alkenylene” groups useful in the presentinvention include, but are not limited to, ethene-1,2-diyl,propene-1,3-diyl, methylene-1,1-diyl, and the like.

As used herein, the term “alkynyl” refers to a hydrocarbon radicalhaving from two to ten carbons and at least one carbon-carbon triplebond, optionally substituted with substituents selected from the groupwhich includes C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆alkylsulfenyl, C₁–C₆ alkylsulfonyl, oxo, aryl, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen and C₁–C₆ perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “alkynyl” as used herein,include but are not limited to acetylenyl, 1-propynyl, 1-butynyl,2-butynyl, 1-pentynyl, and 1-hexynyl.

As used herein, the term “alkynylene” refers to a straight or branchedchain divalent hydrocarbon radical having from two to ten carbon atomsand one or more carbon—carbon triple bonds, optionally substituted withsubstituents selected from the group which includes C₁–C₆ alkyl, C₁–C₆alkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆ alkylsulfenyl, C₁–C₆ alkylsulfonyl,oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, nitro, cyano, halogen and C₁–C₆ perfluoroalkyl,multiple degrees of substitution being allowed. Examples of “alkynylene”as used herein include, but are not limited to, ethyne-1,2-diyl,propyne-1,3-diyl, and the like.

As used herein, the terms “C₁–C₃ alkynylene” and “C₁–C₆ alkynylene”refer to an alkynylene group as defined above containing at least 1, andat most 3 or 6, carbon atoms. Examples of “C₁–C₃ alkynylene” and “C₁–C₆alkynylene” groups useful in the present invention include, but are notlimited to, ethyne-1,2-diyl, propyne-1,3-diyl, and the like.

As used herein, the term “halogen” refers to fluorine (F), chlorine(Cl), bromine (Br), or iodine (I) and the term “halo” refers to thehalogen radicals fluoro (—F), chloro (—Cl), bromo (—Br), and iodo (—I).

As used herein, the term “C₁–C₆ haloalkyl” refers to an alkyl group asdefined above containing at least 1, and at most 6, carbon atomssubstituted with at least one halo group, halo being as defined herein.Examples of branched or straight chained “C₁–C₆ haloalkyl” groups usefulin the present invention include, but are not limited to, methyl, ethyl,propyl, isopropyl, isobutyl and n-butyl substituted independently withone or more halos, e.g., fluoro, chloro, bromo and iodo.

As used herein, the term “C₃–C₇ cycloalkyl” refers to a non-aromaticcyclic hydrocarbon ring having from three to seven carbon atomsoptionally substituted with substituents selected from the group whichincludes C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆alkylsulfenyl, C₁–C₆ alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halo, C₁–C₆ perfluoroalkyl, multiple degrees ofsubstitution being allowed and which optionally includes a C₁–C₆ alkyllinker through which it may be attached. The C₁–C₆ alkyl group is asdefined above. Exemplary “C₃–C₇ cycloalkyl” groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

As used herein, the term “C₃–C₇ cycloalkylene” refers to a non-aromaticalicyclic divalent hydrocarbon radical having from three to seven carbonatoms, optionally substituted with substituents selected from the groupwhich includes C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆alkylsulfenyl, C₁–C₆ alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halo, C₁–C₆ perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “cycloalkylene” as used hereininclude, but are not limited to, cyclopropyl-1,1-diyl,cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl,cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, andthe like.

As used herein, the term “heterocyclic” or the term “heterocyclyl”refers to a non-aromatic three to twelve-membered heterocyclic ringbeing saturated or having one or more degrees of unsaturation containingone or more heteroatomic substitutions selected from S, SO, SO₂, O, orN, optionally substituted with substituents selected from the groupconsisting of C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆alkylsulfenyl, C₁–C₆ alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halo, or C₁–C₆ perfluoroalkyl, multiple degrees ofsubstitution being allowed and which optionally includes a C₁–C₆ alkyllinker through which: it may be attached. Such a ring may be optionallyfused to one or more other “heterocyclic” ring(s) or cycloalkyl ring(s).Examples of “heterocyclic” moieties include, but are not limited to,tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine,pyrrolidine, morpholine, tetrahydrothiopyran, tetrahydrothiophene,di-oxo tetrahydrothiophene, and the like.

As used herein, the term “heterocyclylene” refers to a non-aromaticthree to twelve-membered heterocyclic ring diradical being unsaturatedor having one or more degrees of unsaturation containing-one or moreheteroatoms selected from S, SO, SO₂, O, or N, optionally substitutedwith substituents selected from the group which includes C₁–C₆ alkyl,C₁–C₆ alkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆ alkylsulfenyl, C₁–C₆alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted byalkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, nitro, cyano, halo and C₁–C₆perfluoroalkyl, multiple degrees of substitution being allowed. Such aring may be optionally fused to one or more benzene rings or to one ormore of another “heterocyclic” rings or cycloalkyl rings. Examples of“heterocyclylene” include, but are not limited to,tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl,1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2,4-diyl,piperidine-1,4-diyl, pyrrolidine-1,3-diyl, morpholine-2,4-diyl, and thelike.

As used herein the term “heterocyclic spiro ring system” or“heterocyclyl spiro ring system” refers to a ring system having a threeto twelve-membered non-aromatic heterocyclic ring, being saturated orhaving one or more degrees of unsaturation, containing one or moreheteroatom substitutions selected from S, S(O), S(O)₂, O, or N, and afurther ring being a heterocyclic, or aryl, or heteroaryl, or cycloalkylring, said rings of said ring system having one atom in common and beingoptionally substituted with substituents selected from the groupconsisting of C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆alkylsulfenyl, C₁–C₆ alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halo, aryl, aralkyl, heteroaryl, or C₁–C₆ perfluoroalkyl,multiple degrees of substitution being allowed. Examples of“heterocyclic spiro ring systems” moieties include, but are not limitedto, 1,3-dioxo-2-aza-spiro[4.4]non-2-yl.

As used herein, the term “aryl” refers to an optionally substitutedbenzene ring or to an optionally substituted benzene ring system fusedto one or more optionally substituted benzene rings or optionallysubstituted cycloalkyl rings to form, for example, anthracene,phenanthrene, napthalene, or indan ring systems. Exemplary optionalsubstituents include C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ haloalkyl, C₁–C₆haloalkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆ alkylsulfenyl, C₁–C₆alkylsulfonyl, C₁–C₆ alkylsulfonylamino, arylsulfonoamino, alkylcarboxy,alkylcarboxyamide, oxo, hydroxy, mercapto, amino optionally substitutedby alkyl or acyl, carboxy, tetrazolyl, carbamoyl optionally substitutedby alkyl, aryl, or heteroaryl, aminosulfonyl optionally substituted byalkyl, acyl, aroyl, aroylamino, heteroaroyl, acyloxy, aroyloxy,heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halo, heteroaryl,heterocyclyl, heterocyclic spiro ring system, aryl optionallysubstituted with aryl, arylazo, halo, C₁–C₆ alkyl, C₁–C₆ haloalkyl, orC₁–C₆ alkylsulfonyl, ureido, arylurea, alkylurea, cycloalkylurea,alkylthiourea, aryloxy, heteroaryloxy, or aralkoxy, multiple degrees ofsubstitution being allowed. Examples of “aryl” groups include, but arenot limited to, phenyl, 2-naphthyl, 1-naphthyl, biphenyl, indan, as wellas substituted derivatives thereof.

As used herein, the term “arylene” refers to a benzene ring diradical orto a benzene ring system diradical fused to one or more optionallysubstituted benzene rings, optionally substituted with substituentsselected from the group which includes C₁–C₆ alkyl, C₁–C₆ alkoxy,aryloxy, heteroaryloxy, C₁–C₆ alkylsulfanyl, C₁–C₆ alkylsulfenyl, C₁–C₆alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted byalkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by alkyl,aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl,acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halo,C₁–C₆ perfluoroalkyl, heterocyclyl, heterocyclic spiro ring system,heteroaryl and aryl, multiple degrees of substitution being allowed.Examples of “arylene” include, but are not limited to, benzene-1,4-diyl,naphthalene-1,8-diyl, anthracene-1,4-diyl, and the like.

As used herein, the term “aralkyl” refers to an aryl or heteroarylgroup, as defined herein, attached through a C₁–C₃ alkylene linker,wherein the C₁–C₃ alkylene is as defined herein. Examples of “aralkyl”include, but are not limited to, benzyl, phenylpropyl, 2-pyridylmethyl,3-isoxazolylmethyl, 5-methyl, 3-isoxazolylmethyl, and 2-imidazoylyethyl.

As used herein, the term “heteroaryl” refers to a monocyclic five toseven membered aromatic ring, or to a fused bicyclic or tricyclicaromatic ring system comprising two of such monocyclic five to sevenmembered aromatic rings. These heteroaryl rings contain one or morenitrogen, sulfur, and/or oxygen heteroatoms, where N-oxides and sulfuroxides and dioxides are permissible heteroatom substitutions and may beoptionally substituted with up to three members selected from a groupconsisting of C₁–C₆ alkyl, C₁–C₆ alkoxy, C₁–C₆ alkylsulfanyl, C₁–C₆alkylsulfenyl, C₁–C₆ alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, tetrazolyl, carbamoyloptionally substituted by alkyl, aminosulfonyl optionally substituted byalkyl, acyl, aroyl, aroylamino, heteroaroyl, aryloxy, heteroaryloxy,acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halo,C₁–C₆ perfluoroalkyl, heterocyclyl, heterocyclic spiro ring system,heteroaryl, or aryl, multiple degrees of substitution being allowed.Examples of “heteroaryl” groups used herein include furanyl, thiophenyl,pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl,oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl,isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl, quinolinyl,isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, indazolyl, andsubstituted versions thereof.

As used herein, the term “heteroarylene” refers to a five- toseven-membered aromatic ring diradical, or to a polycyclic heterocyclicaromatic ring diradical, containing one or more nitrogen, oxygen, orsulfur heteroatoms, where N-oxides and sulfur monoxides and sulfurdioxides are permissible heteroaromatic substitutions, optionallysubstituted with substituents selected from the group consisting of:C₁–C₆ alkyl, C₁–C₆ alkoxy, aryloxy, heteroaryloxy, C₁–C₆ alkylsulfanyl,C₁–C₆ alkylsulfenyl, C₁–C₆ alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, tetrazolyl, carbamoyloptionally substituted by alkyl, aminosulfonyl optionally substituted byalkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,alkoxycarbonyl, nitro, cyano, halo, C₁–C₆ perfluoroalkyl, heterocyclyl,heterocyclic spiro ring system, heteroaryl, or aryl, multiple degrees ofsubstitution being allowed. For polycyclic aromatic ring systemdiradicals, one or more of the rings may contain one or moreheteroatoms. Examples of “heteroarylene” used herein are furan-2,5-diyl,thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl,1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl,1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl,pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and thelike.

As used herein, the term “alkoxy” refers to the group R_(a)O—, whereR_(a) is alkyl as defined above and the term “C₁–C₆ alkoxy” refers to analkoxy group as defined herein wherein the alkyl moiety contains atleast 1, and at most 6, carbon atoms. Exemplary C₁–C₆ alkoxy groupsuseful in the present invention include, but are not limited to,methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.

As used herein the term “aralkoxy” refers to the group R_(b)R_(a)O—,where R_(a) is alkyl and R_(b) is aryl as defined above.

As used herein the term “aryloxy” refers to the group R_(a)O—, whereR_(a) is aryl as defined above.

As used herein the term “heteroaryloxy” refers to the group R_(a)O—,where R_(a) is heteroaryl as defined above.

As used herein the term “ureido” refers to the group —NHC(O)NH₂

As used herein, the term “arylurea” refers to the group —NHC(O)NHR_(a)wherein R_(a) is aryl as defined above.

As used herein, the term “arylthiourea” refers to the group—NHC(S)NHR_(a) wherein R_(a) is aryl as defined above.

As used herein, the term “alkylurea” refers to the group —NHC(O)NHR_(a)wherein R_(a) is alkyl as defined above.

As used herein, the term “cycloalkylurea” refers to the group—NHC(O)NHR_(a) wherein R_(a) is cycloalkyl as defined above.

As used herein, the term “C₃–C₇ cycloalkoxy” refers to the groupR_(a)O—, where R_(a) is C₃–C₇ cycloalkyl as defined above. ExemplaryC₃–C₇ cycloalkoxy groups useful in the present invention include, butare not limited to, cyclobutoxy, and cyclopentoxy.

As used herein, the term “haloalkoxy” refers to the group R_(a)O—, whereR_(a) is haloalkyl as defined above and the term “C₁–C₆ haloalkoxy”refers to a haloalkoxy group as defined herein wherein the haloalkylmoiety contains at least 1, and at most 6, carbon atoms. Exemplary C₁–C₆haloalkoxy groups useful in the present invention include, but is notlimited to, trifluoromethoxy.

As used herein, the term “alkylsulfanyl” refers to the group R_(a)S—,where R_(a) is alkyl as defined above and the term “C₁–C₆ alkylsulfanyl”refers to an alkylsulfanyl group as defined herein wherein the alkylmoiety contains at least 1, and at most 6, carbon atoms.

As used herein, the term “haloalkylsulfanyl” refers to the groupR_(a)S—, where R_(a) is haloalkyl as defined above and the term “C₁–C₆haloalkylsulfanyl” refers to a haloalkylsulfanyl group as defined hereinwherein the alkyl moiety contains at least 1, and at most 6, carbonatoms.

As used herein, the term “alkylsulfenyl” refers to the group R_(a)S(O)—,where R_(a) is alkyl as defined above and the term “C₁–C₆ alkylsulfenyl”refers to an alkylsulfenyl group as defined herein wherein the alkylmoiety contains at least 1, and at most 6, carbon atoms.

As used herein, the term “alkylsulfonyl” refers to the groupR_(a)S(O)₂—, where R_(a) is alkyl as defined above and the term “C₁–C₆alkylsulfonyl” refers to an alkylsulfonyl group as defined hereinwherein the alkyl moiety contains at least 1, and at most 6, carbonatoms.

As used herein, the term “alkylsulfonylamino” refers to the group—NHS(O)₂R_(a) wherein R_(a) is alkyl as defined above and the term“C₁–C₆ alkylsulfonylamino” refers to an alkylsulfonylamino group asdefined herein wherein the alkyl moiety contains at least 1, and at most6, carbon atoms.

As used herein, the term “arylsulfonylamino” refers to the group—NHS(O)₂R_(a) wherein R_(a) is aryl as defined above.

As used herein, the term “alkylcarboxyamide” refers to the group—NHC(O)R_(a) wherein R_(a) is alkyl, amino, or amino substituted withalkyl, aryl or heteroaryl as described above.

As used herein the term “alkylcarboxy” refers to the group —C(O)R_(a)wherein R_(a) is alkyl as described above.

As used herein the term “arylazo” refers to the group —N═NR_(a) whereinR_(a) is aryl as described above.

As used herein, the term “oxo” refers to the group ═O.

As used herein, the term “mercapto” refers to the group —SH.

As used herein, the term “carboxyl” refers to the group —C(O)OH.

As used herein, the term “cyano” refers to the group —CN.

As used herein the term “cyanoalkyl” refers to the group —CNR_(a),wherein R_(a) is alkyl as defined above. Exemplary “cyanoalkyl” groupsuseful in the present invention include, but are not limited to,cyanomethyl, cyanoethyl, and cyanoisopropyl.

As used herein, the term “aminosulfonyl” refers to the group —S(O)₂NH₂.

As used herein, the term “carbamoyl” refers to the group —C(O)NH₂.

As used herein, the term “sulfanyl” shall refer to the group —S—.

As used herein, the term “sulfenyl” shall refer to the group —S(O)—.

As used herein, the term “sulfonyl” shall refer to the group —S(O)₂— or—SO₂—.

As used herein, the term “acyl” refers to the group R_(a)C(O)—, whereR_(a) is alkyl, cycloalkyl, or heterocyclyl as defined herein.

As used herein, the term “aroyl” refers to the group R_(a)C(O)—, whereR_(a) is aryl as defined herein.

As used herein, the term “aroylamino” refers to the group R_(a)C(O)NH—,which optionally includes a C₁–C₆ alkyl linker through which it may beattached, where R_(a) is aryl as defined herein.

As used herein, the term “heteroaroyl” refers to the group R_(a)C(O)—,where R_(a) is heteroaryl as defined herein.

As used herein, the term “alkoxycarbonyl” refers to the groupR_(a)OC(O)—, where R_(a) is alkyl as defined herein.

As used herein, the term “acyloxy” refers to the group R_(a)C(O)O—,where R_(a) is alkyl, cycloalkyl, or heterocyclyl as defined herein.

As used herein, the term “aroyloxy” refers to the group R_(a)C(O)O—,where R_(a) is aryl as defined herein.

As used herein, the term “heteroaroyloxy” refers to the groupR_(a)C(O)O—, where R_(a) is heteroaryl as defined herein.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s),which occur, and events that do not occur.

As used herein, the term “physiologically functional derivative” refersto any pharmaceutically acceptable derivative of a compound of thepresent invention, for example, an ester or an amide, which uponadministration to a mammal is capable of providing (directly orindirectly) a compound of the present invention or an active metabolitethereof. Such derivatives are clear to those skilled in the art, withoutundue experimentation, and with reference to the teaching of Burger'sMedicinal Chemistry And Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent that it teaches physiologically functional derivatives.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I) or formula (II) or a salt or physiologically functionalderivative thereof) and a solvent. Such solvents for the purpose of theinvention may not interfere with the biological activity of the solute.Examples of suitable solvents include, but are not limited to, water,methanol, ethanol and acetic acid. Preferably the solvent used is apharmaceutically acceptable solvent Examples of suitablepharmaceutically acceptable solvents include, without limitation, water,ethanol and acetic acid. Most preferably the solvent used is water.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

Certain of the compounds described herein contain one or more chiralatoms, or may otherwise be capable of existing as two enantiomers. Thecompounds of this invention include mixtures of enantiomers as well aspurified enantiomers or enantiomerically enriched mixtures. Alsoincluded within the scope of the invention are the individual isomers ofthe compounds represented by formulae (I) and (II) above as well as anywholly or partially equilibrated mixtures thereof. The present inventionalso covers the individual isomers of the compounds represented by theformulas above as mixtures with isomers thereof in which one or morechiral centers are inverted. Also, it is understood that all tautomersand mixtures of tautomers of the compounds of formulae (I) or (II) areincluded within the scope of the compounds of formulae (I) and (II).

It is to be understood that reference to compounds of formula (I),formula (II) and formula (III) above, following herein, refers tocompounds within the scope of formula (I), formula (II), formula (III),and formulae (IV), (IVa), (IVb), and (IVc) as defined above with respectto X, A, D, R, R¹, R², R³, R^(3a), R⁴, R⁵, R⁶, R⁷, R⁸, R′, R″, R′″, orR″″ unless specifically limited otherwise. It is also understood thatthe following embodiments, including uses and compositions, althoughrecited with respect to formula (I) are also applicable to formula (II),formula (III), and formulae (IV), (IVa), (IVb), and (IVc).

In one embodiment, the compound of formula (I) is a compound of formulaII):

or salt, solvate, or physiologically functional derivative thereof,wherein A and D are as defined above in the first aspect of theinvention.

In one embodiment, the compound of formula (I) is a compound of formula(III):

or salt, solvate, or physiologically functional derivative thereof,wherein A and D are as defined above in the first aspect of theinvention.

In one embodiment, the compound of formula (I) is a compound of formula(IV):

or salt, solvate, or physiologically functional derivative thereof,wherein D, R¹, and R² are as defined above in the first aspect of theinvention and R^(3a) is as defined above in the seventh aspect of theinvention.

In one embodiment, the compound of formula (I) is a compound of formula(IVa):

or salt, solvate, or physiologically functional derivative thereof,wherein D, R¹, R², and R³ are as defined above in the first aspect ofthe invention.

In one embodiment, the compound of formula (I) is a compound of formula(IVb).

or salt, solvate, or physiologically functional derivative thereof,wherein D, R¹, R², and R³ are as defined above in the first aspect ofthe invention.

In one embodiment, the compound of formula (I) is a compound of formula(IVc):

or salt, solvate, or physiologically functional derivative thereof,wherein D is as defined above in the first aspect of the invention andR^(3a) is as defined above in the seventh aspect of the invention.

In one embodiment, X is O. In another embodiment, X is S.

In one embodiment, A is aryl, heteroaryl, or aryl or heteroarylsubstituted with at least one independently selected R³ group. In apreferred embodiment, A is aryl substituted with at least oneindependently selected R³ group. In a more preferred embodiment, A isphenyl substituted with at least one independently selected R³ group. Ina most preferred embodiment, A is phenyl substituted with the group—NHC(O)R⁴, wherein R⁴ is the group NR′″R″″.

In one embodiment, D is hydrogen, halo, aryl, heteroaryl, or aryl orheteroaryl substituted with at least one independently selected R³group. In a preferred embodiment, D is hydrogen, halo, or arylsubstituted with at least one independently selected R³ group. In a morepreferred embodiment, D is aryl substituted with at least oneindependently selected R³ group. In another more preferred embodiment, Dis hydrogen or halo.

In one embodiment, A is aryl, heteroaryl, or aryl or heteroarylsubstituted with at least one independently selected R³ group and D ishydrogen, halo, aryl, heteroaryl, or aryl or heteroaryl substituted withat least one independently selected R³ group. In a preferred embodiment,A is aryl substituted with at least one independently selected R³ groupand D is hydrogen, halo, or aryl substituted with at least oneindependently selected R³ group. In a more preferred embodiment, A isphenyl substituted with at least one independently selected R³ group andD is hydrogen or halo. In another more preferred embodiment, A is phenylsubstituted with at least one independently selected R³ group and D isaryl substituted with at least one independently selected R³ group.

In a most preferred embodiment, A is phenyl substituted with the group—NHC(O)R⁴, wherein R⁴ is the group NR′″R″″ and D is aryl substitutedwith at least one independently selected R³ group. Alternatively, A isphenyl substituted with the group —NHC(O)R⁴, wherein R⁴ is the groupNR′″R″″ and D is hydrogen or halo.

In one embodiment, R¹ is hydrogen, methyl, —C(O)NH₂, —NH₂, or—NHCH₂CH₂NR′″R″″. In a preferred embodiment, R¹ is hydrogen, methyl or—NH₂. In a more preferred embodiment R¹ is hydrogen.

In one embodiment, R² is —NR⁷R⁷. In a preferred embodiment, R² is —NR⁷R⁷wherein the R⁷ groups are selected from hydrogen or C₁–C₆ alkyl. In morepreferred embodiment, R² is —NH₂.

In one embodiment, X is O, A is aryl, heteroaryl, or aryl or heteroarylsubstituted with at least one independently selected R³ group, D ishydrogen, halo, aryl, heteroaryl, or aryl or heteroaryl substituted withat least one independently selected R³ group, R¹ is hydrogen, methyl,—C(O)NH₂, —NH₂, or —NHCH₂CH₂NR′″R″″, and R² is —NR⁷R⁷. In a preferredembodiment, X is O, A is aryl substituted with at least oneindependently selected R³ group, D is hydrogen, halo, or arylsubstituted with at least one independently selected R³ group, R¹ ishydrogen, methyl, —C(O)NH₂, —NH₂, or —NHCH₂CH₂NR′″R″″, and R² is —NR⁷R⁷.In a more preferred embodiment, X is O, A is phenyl substituted with atleast one independently selected R³ group, D is hydrogen or halo, R¹ ishydrogen, methyl or —NH₂, and R² is —NR⁷R⁷ wherein the R⁷ groups areselected from hydrogen or C₁–C₆ alkyl. In another more preferredembodiment, X is O, A is phenyl substituted with at least oneindependently selected R³ group, D is aryl substituted with at least oneindependently selected R³ group, R¹ is hydrogen or methyl, and R² is—NR⁷R⁷ wherein the R⁷ groups are selected from hydrogen or C₁–C₆ alkyl.

In a most preferred embodiment, X is O, A is phenyl substituted with thegroup —NHC(O)R⁴, wherein R⁴ is the group NR′″R″″, D is aryl substitutedwith at least one independently selected R³ group, R¹ is hydrogen, andR² is —NH₂. Alternatively, X is O, A is phenyl substituted with thegroup —NHC(O)R⁴, wherein R⁴ is the group NR′″R″″, D is hydrogen or halo,R¹ is hydrogen, and R² is —NH₂.

In one embodiment, X is S, A is aryl, heteroaryl, or aryl or heteroarylsubstituted with at least one independently selected R³ group, D ishydrogen, halo, aryl, heteroaryl, or aryl or heteroaryl substituted withat least one independently selected R³ group, R¹ is hydrogen, methyl,—C(O)NH₂, —NH₂, or —NHCH₂CH₂NR′″R″″, and R² is —NR⁷R⁷. In a preferredembodiment, X is S, A is aryl substituted with at least oneindependently selected R³ group, D is hydrogen, halo, or arylsubstituted with at least one independently selected R³ group, R¹ ishydrogen, methyl, —C(O)NH₂, —NH₂, or —NHCH₂CH₂NR′″R″″, and R² is —NR⁷R⁷.In a more preferred embodiment, X is S, A is phenyl substituted with atleast one independently selected R³ group, D is hydrogen or halo, R¹ ishydrogen, methyl or —NH₂, and R² is —NR⁷R⁷ wherein the R⁷ groups areselected from hydrogen or C₁–C₆ alkyl. In another more preferredembodiment, X is S. A is phenyl substituted with at least oneindependently selected R³ group, D is aryl substituted with at least oneindependently selected R³ group R¹ is hydrogen, methyl or —NH₂, and R²is —NR⁷R⁷ wherein the R⁷ groups are selected from hydrogen or C₁–C₆alkyl.

In a most preferred embodiment, X is S, A is phenyl substituted with thegroup —NHC(O)R⁴, wherein R⁴ is the group NR′″R″″, D is aryl substitutedwith at least one independently selected R³ group, R¹ is hydrogen, andR² is —NH₂. Alternatively, X is S, A is phenyl substituted with thegroup —NHC(O)R⁴, wherein R⁴ is the group NR′″R″″, D is hydrogen or halo,R¹ is hydrogen, and R² is —NH₂.

Specific examples of compounds of the present invention include thefollowing:

-   4-Amino-3-(4-methoxyphenyl)-2-(3-(methylsulfonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(dimethylamino)phenyl)-2-(4-methoxyphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-chlorophenyl)sulfonylamino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)amino-carbonylamino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(2,3-difluorophenyl)phenyl)-2-(3-sulfamoylphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(3-biphenyl)phenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(4-fluoro-3-(methylsulfonylamino)-phenyl)furo[2,3-d]pyrimidine;    and-   4-Amino-2-(3-cyanophenyl)-3-(4-((2-fluoro-5-(trifluoromethyl)-phenyl)amino    carbonylamino)phenyl)furo[2,3-d]pyrimidine;    or a salt, solvate, or physiologically functional derivative    thereof.

Further specific Examples of compounds of the present invention include:

-   4-Amino-2,3-diphenylfuro[2,3-d]pyrimidine;-   4-Amino-2,3-bis(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2,3-bis(3,4-O-methylidenedioxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2,3-dibutylfuro[2,3-d]pyrimidine;-   4-Amino-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(3-furanyl)-3-(2-furanyl)furo[2,3-d]pyrimidine;-   4-Amino-2,3-bis(4-methyl phenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-methylphenyl)-3-(4-trifluoromethylphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methylphenyl)-2-(4-trifluoromethylphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(2-benzothienyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-biphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(2-chlorophenyl)-3-(4-methoxylphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(2-methoxylphenyl)-3-(4-methoxyl l)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(1-naphthyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(2-naphthyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(4-trifluoromethyloxyphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-2-(3-methoxyphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   3-(3-Acetamidophenyl)-4-amino-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(3,4-dimethoxyphenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-isopropylphenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-butylphenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-methoxyphenyl)-3-(3-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-bromo-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-methoxyphenyl)-3-(2-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-methoxyphenyl)-3-((4-methylthio)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-methoxyphenyl)-3-(1-naphthyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-methoxyphenyl)-3-(2-naphthyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-methoxyphenyl)-3-(4-(trifluoromethyloxy)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(2,5-dimethoxyphenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-methoxyphenyl)-3-(4-(methylsulfonyl)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-2-(4-methoxyphenyl)-3-(4-(phenyloxy)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-methoxyphenyl)-3-(3-pyridyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-cyanophenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-methoxyphenyl)-3-(4-tert-butylphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-methoxyphenyl)-3-((3-fluoro-4-phenyl)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-((4-benzyloxy-3-fluoro)phenyl)-2-(4-methoxyphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-((4-ethylthio)    phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(3-chloro-4-fluorophenyl)-2-(4-meth    oxyphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-2-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-methoxyphenyl)-3-(2-phenylethyn-1-yl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(2-methylphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(2-chlorophenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(2-fluorophenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(3-acetamidophenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(3-pyridyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(2-butylethyn-1-yl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(2-(3-methylbutyl)ethyn-1-yl)-2-(4-methoxyphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(2-(tert-butyl)ethyn-1-yl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(hydroxymethyl)phenyl)-2-(4-methoxyphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(2-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(2-methoxyphenyl)-3-((4-methylthio)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(2-phenylethyn-1-yl)furo[2,3-d]pyrimidine;-   4-Amino-2-(2-butylethyn-1-yl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(2-biphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(3-biphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-(2-carboxyethyl)phenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(4-(methylsulfonyl)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-2-(4-carboxyphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(1-(4-chlorophenyl)-1-hydroxy)methyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-isopropyl    phenyl)-2-(2-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(cyclopentyloxy)phenyl)-2-(2-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(isopropyloxy)phenyl)-2-(2-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Benzyloxycarbonylamino-3-(4-methoxyphenyl)furo[2,3-d]-pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(2-phenylethen-1-yl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(2-phenylethyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(4-(morpholinocarbonyl)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(4-(N-methylcarbamoyl)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(4-(N-(2-(4-imidazolyl)ethyl)carbamoyl)phenyl)furo[2,3-d]pyrimidine;-   2,3-Bis(4-methoxyphenyl)-4,5-dihydro-4-imino-5-methylfuro[2,3-d]pyrimidine;-   3,4-Bis(4-methoxyphenyl)-4-methylaminofuro[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(4-(N-(2-dimethylaminoethyl)-carbamoyl)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(1-hexen-1-yl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-hexyl-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(2,4-dimethoxyphenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(2-methoxypyridin-5-yl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-(dimethylamino)phenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(2,4-dimethoxyphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-methoxyphenyl)-3-(2-methoxypyridin-5-yl)furo[2,3-d]pyrimidine;-   4-Amino-2-((3-chlorophenyl)oxymethyl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-2-((4-fluorophenyl)oxymethyl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-((1-hydroxy-1-phenyl)methyl)-furo[2,3-d]pyrimidine;-   4-Amino-2-(3-carbamoylphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(3-(N-dimethylcarbamoyl)phenyl)-3-(4-methoxyphenyl)    furo[2,3-d]pyrimidine;-   4-Amino-2-(1-methylindol-5-yl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-((2-hydroxymethyl)phenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(3-aminophenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-carboxy-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(2-carboxyphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(3-methoxycarbonylphenyl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-2-(4-methoxyphenyl)-3-(1-methylindol-5-yl)furo[2,3-d]pyrimidine;-   4-Amino-2-(3-carboxyphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(3-(N-(2-(4-imidazolyl)ethyl)carbamoyl)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(3-((4-methylpiperazin-1-yl)-carbonyl)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(3-(N-(2-dimethylaminoethyl)-carbamoyl)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-((2-cyanophenyl)oxymethyl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-2-((2-fluorophenyl)oxymethyl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(3-(N-(4-pyridyl)carbamoyl)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(2-carbamoylphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-carboxy-2-methoxyphenyl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(3-(N-(3-pyridyl)carbamoyl)-phenyl)furo[2,3-d]pyrimidine;-   2-((3-Acetamidophenyl)oxymethyl)-4-amino-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-2-((3-cyanophenyl)oxymethyl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-2-(3-methoxycarbonyl-4-(methylamino)phenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(4-methylamino-3-carboxyphenyl)furo[2,3-d]pyrimidine    hydrochloride;-   4-Amino-2-(4-methoxyphenyl)-3-(4-(methylsulfonylamino)phenyl)    furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(N-(3-methylindazol-5-yl)carbamoyl)furo[2,3-d]pyrimidine;-   4-Amino-2-((1,2-bis(ethoxycarbonyl)hydradino)methyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(diethylamino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(N-phenylcarbamoyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(((5-amino-3-methyl)indazol-1-yl)carbonyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(1-pyrrolizinocarbonyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-((N,N-dicyclohexyl)carbamoyl)furo-[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(N-isopropylcarbamoyl)furo-[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(N-(2-dimethylaminoethyl)carbamoyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-methoxyphenyl)-3-(4-(1-pyrrolidino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(5-indolyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-((2-(phenylamino)ethyl)oxycarbonyl)furo[2,3-d]pyrimidine;-   4-Amino-2-((3-hydroxypiperizin-1-yl)carbonyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-((N-(2-cyanoethyl)-N-phenyl)carbamoyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(3-carbamoylphenyl)furo[2,3-d]pyrimidine;-   2-(3-Acetamidophenyl)-4-amino-3-(4-biphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-((N-(methoxycarbonylmethyl)-N-phenyl)carbamoyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(3-carbamoyl-4-chlorophenyl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-2-(3-aminophenyl)-3-(4-biphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(3-(aminomethyl)phenyl)-3-(4-biphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(4-(dimethylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-((N-(2-(tert-butoxycarbonylamino)ethyl)-N-phenyl)carbamoyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-((N-carboxymethyl-N-phenyl)carbamoyl)furo[2,3-d]pyrimidine;-   4-Amino-2-carbamoyl-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(3-((2-morpholinoethyl)-sulfonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-((2-methyl)benzothiazol-5-yl)furo[2,3-d]pyrimidine;-   4-Amino-2-(6-indolyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(3-carbamoyl-4-fluorophenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(3-carbamoyl-4-fluorophenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-((4-hydroxypiperizin-1-yl)carbonyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-amino-3-(N-methylcarbamoyl)phenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-((N-(carbamoylmethyl)-N-phenyl)carbamoyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-((N-(2-(aminocarbonylamino)ethyl)-N-phenyl)carbamoyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(2-aminoxadiazol-5-yl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-(ethoxycarbonyl)thiazol-2-yl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-2-((4-(4-fluorophenyl)-5-methyl)thiazol-2-yl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(5-indolyl)-3-(4-(3-pyridyl)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(2-imidazolin-2-yl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(2-(phenylamino)oxadiazol-5-yl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(1    H-indeno[3,2-d]thiazol-2-yl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(4-methylthiazol-2-yl)furo[2,3-d]pyrimidine;-   4-Amino-2-((3-(2-(dimethylamino)ethyl)aminocarbonylamino)phenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-((3-(2-(dimethylamino)ethyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(3-(methylsulfonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(4-(N-methylcarbamoyl)thiazol-2-yl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(3-fluorophenyl)phenyl)-2-(3-(methylsulfonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(4-(N-phenylcarbamoyl)thiazol-2-yl)furo[2,3-d]pyrimidine;-   4-Amino-2-(1-benzyl-4,5-dihydro-1H-imidazol-2-yl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(2-oxadiazolyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(5,6,7,7a-tetrahydro-1H-pyrrolo[1,2–C]imidazol-3-yl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-carboxythiazol-2-yl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(3-(methylsulfonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(N-(2-phenylethyl)carbamoyl)-furo[2,3-d]pyrimidine;-   4-Amino-2-(N-(3-fluorophenyl)carbamoyl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-2-(N-(4-chlorophenyl)carbamoyl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(N-(4-methoxyphenyl)carbamoyl)-furo[2,3-d]pyrimidine;-   4-Amino-2-(N-(2-benzoimidazolyl)carbamoyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(2,3-difluorophenyl)phenyl)-2-(4-fluoro-3-(methylsulfonylamino)    phenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(N-(2-hydroxyphenyl)carbamoyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-fluoro-3-(methylsulfonylamino)phenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(4-fluoro-3-(methylsulfonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-((6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)carbonyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(N-(2-carbamoylphenyl)carbamoyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-fluoro-3-(methylsulfonylamino)phenyl)-3-(4-(3-thienyl)    phenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(3-(aminocarbonylamino)phenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(3-(aminocarbonylamino)phenyl)-3-(4-biphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(N-(3-cyanophenyl)carbamoyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(N-(3-pyridyl)carbamoyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(N-(α-cyanobenzyl)carbamoyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(N-(3,5-dimethoxyphenyl)carbamoyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-bi phenyl)-2-(4-methoxy-3-(methylsulfonylamino)    phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(3-((2-fluoro-5-(trifluoromethyl)phenyl)amino    carbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(4-(methylsulfonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(4-(aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-bi phenyl)-2-(3-((4-pyridylcarbonyl)amino)    phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(4-(methylsulfonylamino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-(aminocarbonylamino)phenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(5-benzotriazolyl)-3-(4-biphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(3-(p-toluenesulfonylamino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-2-(5-benzimidazolyl)-3-(4-biphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(4-sulfamoylphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(3-(N-methylsulfonyl)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-fluoro-3-(methylsulfonylamino)phenyl)-3-(4-(2-pyridyl)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(4-((dimethylamino)sulfonylamino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(4-((1-iminoethyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(4-tert-butylphenyl)phenyl)-2-(3-sulfamoylphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(3-((dimethylamino)sulfonylamino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(2-pyridyl)phenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(3-pyridyl)phenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(4-cyanophenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(4-(tetrazol-5-yl)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-biphenyl)-2-(3-(tetrazol-5-yl)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(1-naphthyl)phenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(4-(ethylsulfonyl)phenyl)phenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2,3-bis(4-methoxyphenyl)-6-(ethoxycarbonyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(4,6-bis(trifluoromethyl)phenyl)phenyl)-2-(3-sulfamoyl    phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(2-fluorobiphen-4-yl)phenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2,3-bis(4-methoxyphenyl)-6-carbamoylfuro[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-chlorophenyl)aminocarbonylamino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(4-(tetrazol-5-yl)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-methoxyphenyl)-2-(3-(tetrazol-5-yl)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-fluorobenzoyl)amino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-fluorobenzoyl)amino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2,3-bis(4-methoxyphenyl)-6-methylfuro[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)-6-(methylamino)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-naphthylsulfonyl)amino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(3-acetamidophenyl)phenyl)-2-(3-sulfamoylphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(aminocarbonylamino)phenyl)-2-(4-methoxyphenyl)-furo[2,3-d]pyrimidine;-   4-Amino-2-(4-methoxyphenyl)-3-(4-(phenyl(aminocarbonylamino))-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(cyclohexyl(aminocarbonylamino))phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(butyl(aminocarbonylamino))phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)methyl)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(3-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(aminomethyl)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(3-aminophenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(4-cyanophenyl)-3-(4-((2-fluoro-5-(trifluoromethyl)-phenyl)    aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(phenyl(aminothiocarbonylamino))phenyl)furo[2,3-d]pyrimidine;-   3-(4-nitrophenyl)-4-(phenylamino)furo[2,3-d]pyrimidine;-   4-(methyllamino)-3-(4-nitrophenyl)-furo[2,3-d]pyrimidine;-   3-(4-Aminophenyl)-4-(methylamino)furo[2,3-d]pyrimidine;-   3-(4-Aminophenyl)-4-(phenylamino)furo[2,3-d]pyrimidine;-   3-(4-Aminophenyl)-4-(dimethylamino)furo[2,3-d]pyrimidine;-   4-(Dimethylamino)-3-(4-nitrophenyl)furo[2,3-d]pyrimidine;-   3–4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-phenyl)-4-(methylamino)furo[2,3-d]pyrimidine;-   3-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-phenyl)-4-(phenylamino)furo[2,3-d]pyrimidine;-   4-(Dimethylamino)-3-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4,5-Dihydro-3-(4-nitrophenyl)-4-oxofuro[2,3-d]pyrimidine;-   3-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-phenyl)-6-(methylthio)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-ethylphenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-(dimethylamino)phenyl)aminocarbonylamino)-phenyl)furo[2,3-d]pyrimidine;-   3-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-phenyl)-6-(methylsulfonyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-methoxyphenyl)aminocarbonylamino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2,2,4,4-tetrafluoro-1,3-benzodioxan-5-yl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-(phenyloxy)phenyl)aminocarbonylamino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-Indanyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2,5-bis(trifluoromethyl)phenyl)aminocarbonylamino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-(phenyloxy)phenyl)aminocarbonylamino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2,5-dimethoxyphenyl)aminocarbonylamino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-(trifluoromethyl)phenyl)aminocarbonylamino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-(trifluoromethylthio)phenyl)aminocarbonylamino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3,4-(methylenedioxy)phenyl)aminocarbonylamino)-phenyl)furo[2,3-d]pyrimidine;-   3-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-phenyl)-6-(methylamino)furo[2,3-d]pyrimidine;-   6-((2-(Dimethylamino)ethyl)amino)-3-(4-((2-fluoro-5-(trifluoromethyl)    phenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-chlorophenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-chloro-5-nitrophenyl)aminocarbonylamino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-chlorophenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-chloro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenyl)-furo[2,3-d]pyrimidine;-   3-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-phenyl)-6-(((2,4,6-trimethoxyphenyl)methyl)amino)furo[2,3-d]pyrimidine;-   6-Amino-3-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-aminophenyl)-6-(methylthio)furo[2,3-d]pyrimidine;-   4-Amino-2-bromo-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-tert-butylthiazol-2-yl)aminocarbonylamino)-phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-thienyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;    and-   4-Amino-2-bromo-3-(4-((5-indanyl)aminocarbonylamino)phenyl)-furo[2,3-d]pyrimidine;    or a salt, solvate, or physiologically functional derivative    thereof.

Further specific Examples of compounds of the present invention include:

-   4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonyl-amino)phenyl)-6-(((2,4,6-trimethoxyphenyl)methyl)amino)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)-2-(3-pyridyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)-2-vinylfuro[2,3-d]pyrimidine;-   4-Amino-2-(1,2-dihydroxyethyl)-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-carboxy-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)-2-iodofuro[2,3-d]pyrimidine;-   4-Amino-2-(4-carboxyphenyl)-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-carbamoyl-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2.3-d]pyrimidine;-   4-Amino-2-(N-(carbamoylmethyl)carbamoyl)-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-6-dimethylamino-3-(4-((2-fluoro-5-(trifluoromethyl)-phenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-6-((2-(dimethylamino)ethyl)amino)-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonyl-amino)phenyl)-6-((2-(methylsulfonylamino)ethyl)amino)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonyl-amino)phenyl)-6-((3-(methylsulfinyl)propyl)amino)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonyl-amino)phenyl)-6-((3-(methylthio)propyl)amino)furo[2,3-d]pyrimidine;-   4-Amino-2-chloro-3-(4-((3-phenyl-1,2,4-thiadiazol-5-yl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-tert-butylisoxazol-3-yl)aminocarbonyl-amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-fluorobenzoyl)amino)phenyl)-2-(3-pyridyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-fluorobenzenesulfonyl)amino)phenyl)-2-(3-pyridyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(3-pyridyl)-3-(4-((2-thienylsulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2,3-dichlorobenzenesulfonyl)amino)phenyl)-2-(3-pyridyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(2-methoxypyridin-5-yl)-3-((4-(phenylsulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-2-(3-pyridyl)-3-((4-((1,2,3,4-tetrahydroisoquinolin-7-yl)sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-fluoro-5-methoxyphenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(3-((4-chlorophenyl)aminocarbonylamino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(3-((phenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(3-((cyclohexyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(3-((butyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(3-((tert-butyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(3-(aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(3-((5-indanyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(3-((5-tert-butylisoxazol-3-yl)aminocarbonylamino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-cyanophenyl)aminocarbonylamino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-acetylphenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-(methoxycarbonyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-fluorophenyl)aminocarbonylamino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-methoxyphenyl)aminocarbonylamino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-methoxyphenylacetyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-thienylacetyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(((5-methyl-2-phenyloxazol-4-yl)acetyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(((3,5-bis-(trifluoromethyl)phenyl)acetyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((benzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2,3-dichlorobenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2,5-dichlorobenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(((5-chlorothiophene-2-sulfonyl)acetyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(((2,5-dichlorothiophene-3-sulfonyl)acetyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-fluorobenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3,4-dichlorobenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-methoxybenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((7-chloro-benzo[1,2,5]oxadiazole-4-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-methoxybenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-chloro-1,3-dimethylpyrazole-4-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4,5-dichlorothiophene-2-sulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-phenylethenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3,5-dichlorophenylsulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-(methoxycarbonyl)thiophene-3-sulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-chlorobenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((1-methyl-1H-imidazole-4-sulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-chlorobenzo[1,2,5]oxadiazole-4-sulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3,5-dimethoxybenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2,5-dimethoxybenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-chloro-4-fluorobenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-chloro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-(methoxycarbonyl)-3-methoxythiophene-2-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-(1-methyl-5-(trifluoromethyl)pyrazol-3-yl)thiophene-2-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-bromo-6-chloropyridine-3-sulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2,3,4,5,6-pentafluorobenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-(trifluoromethoxy)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((thiophene-2-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-isopropylbenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((quinoline-8-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-nitro-4-(trifluoromethyl)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2,4,6-trimethylbenzenesulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-bromo-2-methoxybenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-propylbenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-bromo-2,5-difluorobenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2,6-dichloro-4-(trifluoromethyl)benzenesulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-(trifluoromethoxy)benzenesulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3,5-dimethylisoxazole-4-sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-acetylbenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2,4-dichlorobenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3,5-bis-(trifluoromethyl)benzenesulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-(N-(benzoyl)aminomethyl)thiophene-2-sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-(acetylamino)-4-methylthiazole-5-sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-chloro-4-fluorobenzenesulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-ethylbenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3,5-bis-(trifluoromethyl)phenylmethyl)sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-tert-butylbenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-nitrophenylmethyl)sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-(isoxazol-3-yl)thiophene-2-sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((benzo[1,2,5]thiadiazole-4-sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-cyanobenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((benzo[1,4]dioxan-6-sulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-(2-pyridyl)thiophene-2-sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-(trifluoromethyl)phenylmethyl)sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3,5-dichlorophenylmethyl)sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-(N-(4-chlorobenzoyl)aminomethyl)thiophene-2-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2,6-dichlorobenzenesulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-(benzenesulfonyl)thiophene-2-sulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-bromo-2-ethylbenzenesulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-chloro-2-methylbenzenesulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-bromothiophene-2-sulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-fluorobenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-chlorobenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-(2-methylthio-pyrimidin-4-yl)thiophene-2-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-(5-(trifluoromethyl)pyridine-2-sulfonyl)thiophene-2-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((benzo[1,2,5]oxadiazole-4-sulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2,5-dimethylbenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-(2-methylthiazol-4-yl)thiophene-2-sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-(5-trifluoromethyl-isoxazol-3-yl)thiophene-2-sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-methoxy-5-methylbenzenesulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2,4-dichloro-5-methylbenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-fluoro-2-methylbenzenesulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-chloronaphthalenesulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-(3,5-dichlorophenoxy)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-(4-chlorophenoxy)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(((4-pyridylmethyl)sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-(2-pyridyloxy)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-([1,2,3]thiadiazol-4-yl)thiophene-2-sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-(4-cyano-1-methyl-5-methylthio-1H-pyrazol-3-yl)thiophene-2-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-(4-chlorophenyl)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-(4-pyridyloxy)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-butoxybenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-acetamide-3-chlorobenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-(trifluoromethyl)phenylmethyl)sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-chlorophenylmethyl)sulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3,4-dichlorophenylmethyl)sulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-fluorophenylmethyl)sulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((6-(dimethylamino)naphthalene-1-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((isoquinoline-5-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((1-naphthalenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((phenylmethyl)sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(((2-fluoro-5-(trifluoromethyl)phenylmethyl)-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-(3,4-dichlorophenoxy)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-(2-chlorothiazol-5-ylmethoxy)benzenesulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-(3,4-dichlorophenyl)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-(trifluoromethyl)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((1,1-dioxo-tetrahydro-1/-thiophene-3-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-(phenylazo)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2,5-dibromo-3,6-difluorobenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-bromo-2-(trifluoromethoxy)benzenesulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-chloro-4-cyanobenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2,3,5,6-tetramethylbenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3,5-dichloro-2-hydroxybenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-chloro-4-(1,3-dioxo-2-aza-spiro(4,4)non-2-yl)benzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(((2-chloro-5-(trifluoromethyl)phenylmethyl)-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(((p-tolylmethyl)sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(((1,2-dimethyl-1H-imidazol-4-yl)sulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)thiophene-2-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-(((4-butylbenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((5-indanyl)aminocarbonylamino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-methylphenyl)aminocarbonylamino)phenyl)-thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-methylphenyl)aminocarbonylamino)phenyl)-thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino)-phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-chloro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-(((2,5-difluorophenyl)acetyl)amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)benzoyl)amino)-phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-(benzoylamino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((2,6-difluorobenzoyl)amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-(((S)-2-amino-2-phenylacetyl)amino)phenyl)-thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-(((1S,2S)-2-phenyl-cyclopropanecarbonyl)amino)-phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((2,5-difluorobenzoyl)amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-(((R)-2-amino-2-phenylacetyl)amino)phenyl)-thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((1-phenyl-cyclopropanecarbonyl)amino)-phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-(((2,6-difluorophenyl)acetyl)amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((phenylacetyl)amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-(((3,5-bis-(trifluoromethyl)phenyl)acetyl)amino)-phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-(((2,4-bis-(trifluoromethyl)phenyl)acetyl)amino)-phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-(((3-(trifluoromethylthio)phenyl)acetyl)amino)-phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-(((1R,2R)-2-phenyl-cyclopropanecarbonyl)amino)-phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-(((E)-3-(2-chlorophenyl)acryloyl)amino)-phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-(((E)-3-(3-chlorophenyl)acryloyl)amino)-phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-(((E)-3-phenylacryloyl)amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((1-phenylcyclopentanecarbonyl)amino)-phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-phenylisobutyryl)amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-(((2-fluoro-5-(trifluoromethyl)phenyl)acetyl)amino)-phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-(((2,5-dichlorothiophene-3-yl)carbonyl)amino)-phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-(((bicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)carbonyl)-amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-phenylbutyryl)amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-(((5-methyl-[1,3,4]thiadiazol-2-yl)carbonyl)amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-(((5-tert-butyl-2-methyl-2H-pyrazol-3-yl)carbonyl)amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-(4-methyl-piperazin-1-yl-methyl)benzoyl)amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-cyanobenzoyl)amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((2-methoxybenzoyl)amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-chlorobenzoyl)amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-methoxybenzoyl)amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((4-(trifluoromethoxy)benzoyl)amino)phenyl)-thieno[2.3-d]pyrimidine;-   4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonyl(N-methylamino))phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((3-ethylphenyl)aminocarbonyl(N-methylamino))-phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((1-(3,4-dichlorophenyl)-cyclopropanecarbonyl)amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((1-(2,5-difluorophenyl)-cyclopropanecarbonyl)amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((1-(3,5-bis-(trifluoromethyl)phenyl)-cyclopropanecarbonyl)amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((1-(3-chlorophenyl)cyclopropanecarbonyl)amino)-phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((1-(3-(trifluoromethyl)phenyl)-cyclopropanecarbonyl)amino)phenyl)thieno[2,3-d]pyrimidine;-   4-Amino-3-(4-((1-(3,4-dichlorophenyl)-cyclopropanecarbonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((1-(2,5-difluorophenyl)-cyclopropanecarbonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((1-(3,5-bis-(trifluoromethyl)phenyl)-cyclopropanecarbonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((1-(3-chlorophenyl)cyclopropanecarbonyl)amino)-phenyl)furo[2,3-d]pyrimidine;-   4-Amino-3-(4-((1-phenylcyclopropanecarbonyl)amino)-phenyl)furo[2,3-d]pyrimidine;    and-   4-Amino-3-(4-((1-(3-(trifluoromethyl)phenyl)-cyclopropanecarbonyl)amino)phenyl)furo[2,3-d]pyrimidine;-   or a salt, solvate, or physiologically functional derivative    thereof.

Typically, the salts of the present invention are pharmaceuticallyacceptable salts. Salts encompassed within the term “pharmaceuticallyacceptable salts” refer to non-toxic salts of the compounds of thisinvention. Salts of the compounds of the present invention may compriseacid addition salts derived from a nitrogen on a substituent in thecompound of formula (I). Representative salts include the followingsalts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, monopotassium maleate,mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, potassium, salicylate, sodium, stearate, subacetate,succinate, tannate, tartrate, teoclate, tosylate, triethiodide,trimethylammonium and valerate. Other salts, which are notpharmaceutically acceptable, may be useful in the preparation ofcompounds of this invention and these form a further aspect of theinvention.

While it is possible that, for use in therapy, therapeutically effectiveamounts of a compound of formula (I), as well as salts, solvates andphysiological functional derivatives thereof, may be administered as theraw chemical, it is possible to present the active ingredient as apharmaceutical composition. Accordingly, the invention further providespharmaceutical compositions, which include therapeutically effectiveamounts of compounds of the formula (I) and salts, solvates andphysiological functional derivatives thereof, and one or morepharmaceutically acceptable carriers, diluents, or excipients. Thecompounds of the formula (I) and salts, solvates and physiologicalfunctional derivatives thereof, are as described above. The carrier(s),diluent(s) or excipient(s) must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof. In accordance with another aspectof the invention there is also provided a process for the preparation ofa pharmaceutical formulation including admixing a compound of theformula (I), or salts, solvates and physiological functional derivativesthereof, with one or more pharmaceutically acceptable carriers, diluentsor excipients.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to700 mg, more preferably 5 mg to 100 mg of a compound of the formula (I),depending on the condition being treated, the route of administrationand the age, weight and condition of the patient, or pharmaceuticalformulations may be presented in unit dose forms containing apredetermined amount of active ingredient per unit dose. Preferred unitdosage formulations are those containing a daily dose or sub-dose, asherein above recited, or an appropriate fraction thereof, of an activeingredient Furthermore, such pharmaceutical formulations may be preparedby any of the methods well known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s).

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additive such aspeppermint oil or natural sweeteners or saccharin or other artificialsweeteners, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of formula (I), and salts, solvates and physiologicalfunctional derivatives thereof, can also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compounds of formula (I) and salts, solvates and physiologicalfunctional derivatives thereof may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986).

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations are preferably applied as a topical ointmentor cream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles and mouth washes.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a coarse powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e. by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurised aerosols, nebulizers orinsufflators.

Pharmaceutical formulations adapted for vaginal. administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavouringagents.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors including, for example,the age and weight of the animal, the precise condition requiringtreatment and its severity, the nature of the formulation, and the routeof administration, and will ultimately be at the discretion of theattendant physician or veterinarian However, an effective amount of acompound of formula (I) for the treatment of neoplastic growth, forexample colon or breast carcinoma, will generally be in the range of 0.1to 100 mg/kg body weight of recipient (mammal) per day and more usuallyin the range of 1 to 10 mg/kg body weight per day. Thus, for a 70 kgadult mammal, the actual amount per day would usually be from 70 to 700mg and this amount may be given in a single dose per day or more usuallyin a number (such as two, three, four, five or six) of sub-doses per daysuch that the total daily dose is the same. An effective amount of asalt or solvate, or physiologically functional derivative thereof, maybe determined as a proportion of the effective amount of the compound offormula (I) per se. It is envisaged that similar dosages would beappropriate for treatment of the other conditions referred to above.

The compounds of the present invention and their salts and solvates, andphysiologically functional derivatives thereof, may be employed alone orin combination with other therapeutic agents for the treatment of theabove-mentioned conditions. In particular, in anti-cancer therapy,combination with other chemotherapeutic, hormonal or antibody agents isenvisaged as well as combination with surgical therapy and radiotherapy.Combination therapies according to the present invention thus comprisethe administration of at least one compound of formula (I) or apharmaceutically acceptable salt or solvate thereof, or aphysiologically functional derivative thereof, and the use of at leastone other cancer treatment method. Preferably, combination therapiesaccording to the present invention comprise the administration of atleast one compound of formula (I) or a pharmaceutically acceptable saltor solvate thereof, or a physiologically functional derivative thereof,and at least one other pharmaceutically active agent, preferably ananti-neoplastic agent. The compound(s) of formula (I) and the otherpharmaceutically active agent(s) may be administered together orseparately and, when administered separately this may occursimultaneously or sequentially in any order. The amounts of thecompound(s) of formula (I) and the other pharmaceutically activeagent(s) and the relative timings of administration will be selected inorder to achieve the desired combined therapeutic effect.

The compounds of the Formula (I) or salts, solvates, or physiologicallyfunctional derivatives thereof and at least one additional cancertreatment therapy may be employed in combination concomitantly orsequentially in any therapeutically appropriate combination with suchother anti-cancer therapies. In one embodiment, the other anti-cancertherapy is at least one additional chemotherapeutic therapy includingadministration of at least one anti-neoplastic agent. The administrationin combination of a compound of formula (I) or salts, solvates, orphysiologically functional derivatives thereof with otheranti-neoplastic agents may be in combination in accordance with theinvention by administration concomitantly in (1) a unitarypharmaceutical composition including both compounds or (2) separatepharmaceutical compositions each including one of the compounds.Alternatively, the combination may be administered separately in asequential manner wherein one anti-neoplastic agent is administeredfirst and the other second or vice versa. Such sequential administrationmay be close in time or remote in time.

Anti-neoplastic agents may induce anti-neoplastic effects in acell-cycle specific manner, i.e., are phase specific and act at aspecific phase of the cell cycle, or bind DNA and act in a noncell-cycle specific manner, i.e., are non-cell cycle specific andoperate by other mechanisms.

Anti-neoplastic agents useful in combination with the compounds andsalts, solvates or physiologically functional derivatives thereof offormula I include the following:

(1) cell cycle specific anti-neoplastic agents include, but are notlimited to, diterpenoids such as paclitaxel and its analog docetaxel;vinca alkaloids such as vinblastine, vincristine, vindesine, andvinorelbine; epipodophyllotoxins such as etoposide and teniposide;fluoropyrimidines such as 5-fluorouracil and fluorodeoxyuridine ;antimetabolites such as allopurinol, fludurabine, methotrexate,cladrabine, cytarabine, mercaptopurine and thioguanine; andcamptothecins such as 9-amino camptothecin, irinotecan, topotecan,CPT-11 and the various optical forms of 7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecin;

(2) cytotoxic chemotherapeutic agents including, but not limited to,alkylating agents such as melphalan, chlorambucil, cyclophosphamide,mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomustine,and dacarbazine; anti-tumour antibiotics such as doxorubicin,daunomycin, epirubicin, idarubicin, mitomycin-C, dacttinomycin andmithramycin; and platinum coordination complexes such as cisplatin,carboplatin, and oxaliplatin; and

(3) other chemotherapeutic agents including, but not limited to,anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifeneand iodoxyfene; progestrogens such as megestrol acetate; aromataseinhibitors such as anastrozole, letrazole, vorazole, and exemestane;antiandrogens such as flutamide, nilutamide, bicalutamide, andcyproterone acetate; LHRH agonists and antagagonists such as goserelinacetate and luprolide, testosterone 5α-dihydroreductase inhibitors suchas finasteride; metalloproteinase inhibitors such as marimastat;antiprogestogens; urokinase plasminogen activator receptor functioninhibitors; growth factor function inhibitors such as inhibitors of thefunctions of hepatocyte growth factor; erb-B2, erb-B4, epidermal growthfactor receptor (EGFR), platelet derived growth factor receptor (PDGFR),vascular endothelial growth factor receptor (VEGFR, and TIE-2 (otherthan those VEGFR and TIE-2 inhibitors described in the presentinvention); and other tyrosine kinase inhibitors such as inhibitors ofCDK2 and CDK4 inhibitors.

The compounds of formula (I) and salts, solvates and physiologicalfunctional derivatives thereof, are believed to have anticancer activityas a result of inhibition of the protein kinase TIE-2 and/or VEGFR-2 andits effect on selected cell lines whose growth is dependent on TIE-2and/or VEGFR-2 protein kinase activity.

The present invention thus also provides compounds of formula (I) andpharmaceutically acceptable salts or solvates thereof, orphysiologically functional derivatives thereof, for use in medicaltherapy, and particularly in the treatment of disorders mediated by atleast one of inappropriate TIE-2 and VEGFR-2 activity.

The inappropriate TIE-2 and/or VEGFR-2 activity referred to herein isany TIE-2 and/or VEGFR-2 activity that deviates from the normal TIE-2and/or VEGFR-2 activity expected in a particular mammalian subjectInappropriate TIE-2 and/or VEGFR-2 activity may take the form of, forinstance, an abnormal increase in activity, or an aberration in thetiming and or control of TIE-2 and/or VEGFR-2 activity. Suchinappropriate activity may result then, for example, from overexpressionor mutation of the protein kinase leading to inappropriate oruncontrolled activation. Furthermore, it is also understood thatunwanted TIE-2 and/or VEGFR-2 activity may reside in an abnormal source,such as a malignancy. That is, the level of TIE-2 and/or VEGFR-2activity does not have to be abnormal to be considered inappropriate,rather the activity derives from an abnormal source. In a like manner,the inappropriate angiogenesis referred to herein is any angiogenicactivity that deviates from the normal angiogenic activity expected in aparticular mammalian subject Inappropriate angiogenesis may take theform of, for instance, an abnormal increase in activity, or anaberration in the timing and or control of angiogenic activity. Suchinappropriate activity may result then, for example, from overexpressionor mutation of a protein kinase leading to inappropriate or uncontrolledactivation. Furthermore, it is also understood that unwanted angiogenicactivity may reside in an abnormal source, such as a malignancy. Thatis, the level of angiogenic activity does not have to be abnormal to beconsidered inappropriate, rather the activity derives from an abnormalsource.

The present invention is directed to methods of regulating, modulating,or inhibiting TIE-2 and/or VEGFR-2 for the prevention and/or treatmentof disorders related to unregulated TIE-2 and/or VEGFR-2 activity. Inparticular, the compounds of the present invention can also be used inthe treatment of certain forms of cancer. Furthermore, the compounds ofthe present invention can be used to provide additive or synergisticeffects with certain existing cancer chemotherapies, and/or be used torestore effectiveness of certain existing cancer chemotherapies andradiation.

The compounds of the present invention are also useful in the treatmentof one or-more diseases afflicting mammals which are characterized bycellular proliferation in the area of disorders associated withneo-vascularization and/or vascular permeability including blood vesselproliferative disorders including arthritis and restenosis; fibroticdisorders including hepatic cirrhosis and atherosclerosis; mesangialcell proliferative disorders include glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombotic microangiopathysyndromes, organ transplant rejection and glomerulopathies; andmetabolic disorders include psoriasis, diabetes mellitus, chronic woundhealing, inflammation and neurodegenerative diseases.

A further aspect of the invention provides a method of treatment of amammal suffering from a disorder mediated by at least one ofinappropriate TIE-2 and VEGFR-2 activity, including susceptiblemalignancies, which includes administering to said subject an effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt, solvate, or a physiologically functional derivative thereof. In apreferred embodiment, the disorder is cancer.

A further aspect of the invention provides a method of treatment of amammal suffering from cancer which includes administering to saidsubject an effective amount of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof, or aphysiologically functional derivative thereof.

A further aspect of the present invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, or a physiologically functional derivative thereof, in thepreparation of a medicament for the treatment of a disordercharacterized by at least one of inappropriate TIE-2 and VEGFR-2activity. In a preferred embodiment, the disorder is cancer.

A further aspect of the present invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, or a physiologically functional derivative thereof, in thepreparation of a medicament for the treatment of cancer and malignanttumors.

The mammal requiring treatment with a compound of the present inventionis typicaltly a human being.

In another embodiment, therapeutically effective amounts of thecompounds of formula (I) or salts, solvates or physiologically derivedderivatives thereof and agents which inhibit growth factor receptorfunction may be administered in combination to a mammal for treatment ofa disorder mediated by at least one of inappropriate TIE-2 and VEGFR-2activity, for instance in the treatment of cancer. Such growth factorreceptors include, for example, EGFR, PDGFR, erbB2, erbB4, VEGFR, and/orTIE-2. Growth factor receptors and agents that inhibit growth factorreceptor function are described, for instance, in Kath, John C., Exp.Opin. Ther. Patents (2000) 10(6):803–818 and in Shawver et al DDT Vol 2,No. 2 February 1997.

The compounds of the formula (I) or salts, solvates, or physiologicallyfunctional derivatives thereof and the agent for inhibiting growthfactor receptor function may be employed in combination concomitantly orsequentially in any therapeutically appropriate combination. Thecombination may be employed in combination in accordance with theinvention by administration concomitantly in (1) a unitarypharmaceutical composition including both compounds or (2) separatepharmaceutical compositions each including one of the compounds.Alternatively, the combination may be administered separately in asequential manner wherein one is administered first and the other secondor vice versa. Such sequential administration may be close in time orremote in time.

In another aspect of the present invention, there is provided a methodof treating a disorder in a mammal, said disorder being mediated byinappropriate angiogenesis, including: administering to said mammal atherapeutically effective amount of a compound of formula (I), or asalt, solvate or physiologically functional derivative thereof. In oneembodiment, the inappropriate angiogenic activity is due to at least oneof inappropriate VEGFR1, VEGFR2, VEGFR3, or TIE-2 activity. In anotherembodiment, the inappropriate angiogenesis is due to inappropriateVEGFR2 and TIE-2 activity. In a further embodiment, the method furtherincludes administering a therapeutically effective amount of a VEGFR2inhibitor along with the compounds of formula (I) or salts, solvates orphysiologically functional derivatives thereof. Preferably the disorderis cancer.

In another aspect of the present invention, there is provided the use ofa compound of formula (I), or a salt, solvate or physiologicallyfunctional derivative thereof in the preparation of a medicament for usein treating a disorder in a mammal, said disorder being characterized byinappropriate angiogenesis. In one embodiment, the inappropriateangiogenic activity is due to at least one of inappropriate VEGFR1,VEGFR2, VEGFR3 or TIE-2 activity. In another embodiment, theinappropriate angiogenesis is due to inappropriate VEGFR2 and TIE-2activity. In a further embodiment, the use further includes use of aVEGFR2 inhibitor to prepare said medicament

The combination of a compound of formula (I) or salts, solvates, orphysiologically functional derivatives thereof with a VEGFR2 inhibitormay be employed in combination in accordance with the invention byadministration concomitantly in (1) a unitary pharmaceutical compositionincluding both compounds or (2) separate pharmaceutical compositionseach including one of the compounds. Alternatively, the combination maybe administered separately in a sequential manner wherein one isadministered first and the other second or vice versa. Such sequentialadministration may be close in time or remote in time.

The compounds of this invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the invention are prepared in the WorkingExamples.

Compounds of general formula (I) may be prepared by methods known in theart of organic synthesis as set forth in part by the following synthesisschemes. In all of the schemes described below, it is well understoodthat protecting groups for sensitive or reactive groups are employedwhere necessary in accordance with general principles of chemistry.Protecting groups are manipulated according to standard methods oforganic synthesis (T. W. Green and P. G. M. Wuts (1991) ProtectingGroups in Organic Synthesis, John Wiley & Sons). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selection ofprocesses as well as the reaction conditions and order of theirexecution shall be consistent with the preparation of compounds ofFormula (I). Those skilled in the art will recognize if a stereocenterexists in compounds of Formula (I). Accordingly, the present inventionincludes both possible stereoisomers and includes not only racemiccompounds but the individual enantiomers as well. When a compound isdesired as a single enantiomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be effected by any suitable method known in theart See, for example, Stereochemistry of Organic Compounds by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

Compounds of Formula (I) can be prepared according to the syntheticsequences illustrated in Schemes 1–4. Schemes 1–4 show general routesfor the synthesis of the targeted furo[2,3-d]pyrimidines. Specificdetail of synthetic routes according to Schemes 1–4 are shown in theExamples following wherein furo[2,3-d]pyrimidine compound exampleshaving Tie2 and/or VEGFR-2 inhibitory activity were prepared.

The synthesis of the furo[2,3-d]pyrimidine scaffold having equivalentaryl groups at the C-2 and C-3 position is illustrated as shown inScheme-1. This method is based on synthesis reported in the references:K. Gewald, Chem. Ber., 99, 1002 (1996); T. I. Temnikova, Yu. A.Sharanin, and V. S. Karaban, J. Org. Chem. USSR, 651–654 (1967) and ibd,1938–1945 (1967); X. Feng, J.-C. Lancelot, H. Prunier, and S. Rault. J.Heterocyclic Chem., 33, 2007 (1996); J. Prousek, A. Jurascek, and J.Kovac, Collect. Czech. Chem. Commun., 45 (5), 1581–1588 (1980). Thisscheme can serve as a route to produce various derivatives starting fromdiaryl-α-hydroxyketones through 2-amino-3-cyano-4,5-diarylfurans.

Other effective synthetic routes were reported at: T. Matsuda, K.Yamagata, Y. Tomioka, M. Yamazaki, Chem. Pharm. Bull., 33 (3), 937–943(1985) and are illustrated in Scheme-2 and Scheme-3. According to thesemethods, a variety of diaryl-furo[2,3-d]pyrimidines substituted at C-2and C-3 can be synthesized. The effective syhthesis of 3-arylfuro[2,3-d]pyrimidine was achieved by the route as shown in Scheme-2. Inthis route, the cyclization to the desired scaffold proceeded smoothlyand subsequent halogenations at C-2 were achieved successively.

As indicated above Scheme 1 describes the synthesis of compounds offormula I wherein A and D are equivalent aryl groups (as indicated bythe double arrows phenyl is utilized for A and D by way of Example)wherein the substituents -a, -b represent any substituents describedherein within the scope of the definition of A and D as described above.

As indicated above Scheme 2 describes the synthesis of compounds offormula I wherein A is an aryl group (as indicated by the scheme phenylis utilized for A by way of Example) wherein the substituent -arepresents any substituents described herein within the scope of thedefinition of A as described above. As those skilled in the art willrecognize, various D substituents are available by replacement of thehalo group according to procedures known in the art.

The analogous route illustrated in Scheme-3 also afforded the desired4-amino-2-arylfuro[2,3-d]pyrimidines as key intermediates forderivatizations at C-3.

Derivatization at C-4 and C-6 can be achieved by the convenientsynthetic route shown in Scheme-4. This route was reported at: D.Dauzonne and A. Adam-Launay, Tetrahedron, 48 (15), 3069–3080 (1992).

Wherein A, D, R¹, and R² are as described above for formula (I); and -a,and -e are any appropriate substituent within the scope of theinvention.

The thieno[2,3-d]pyrimidines of the present invention may be prepared bythe stepwise Gewald thiophene ring procedure described by Zhang andHarper (Bioorg. Med. Chem. Lett. (1997), 7, 1629–1634) and in Scheme 5.Knoevenagel condensation of malonodinitrile and a substitutedacetophenone yielded the desired dicyanopropene. Upon heating withsulfur in DMF, the propene was converted to the substituted thiophene,which underwent condensation with formamide to generate the bicyclicthiophenopyrimidine. This system could then be derivatized usingcommonly known synthetic methods.

Certain embodiments of the present invention will now be illustrated byway of example only. The physical data given for the compoundsexemplified is consistent with the assigned structure of thosecompounds.

EXAMPLES

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification.

Specifically, the following abbreviations may be used in the examplesand throughout the specification:

g (grams); mg (milligrams); L (liters); mL (milliliters); μL(microliters); psi (pounds per square inch); M (molar); mM (millimolar);i. v. (intravenous); Hz (Hertz); MHz (megahertz); mol (moles); mmol(millimoles); rt (room temperature); min (minutes); h (hours); mp(melting point); TLC (thin layer chromatography); T_(r) (retentiontime); RP (reverse phase); MeOH (methanol); i-PrOH (isopropanol); TEA(triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroaceticanhydride); THF (tetrahydrofuran); DMSO (dimethylsulfoxide); AcOEt(ethyl acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane); DCE(dichloroethane); DMF (N,N-dimethylformamide); DMPU(N,N′-dimethylpropyleneurea); (CDI (1,1-carbonyldiimidazole); IBCF(isobutyl chloroformate); HOAc (acetic acid); HOSu(N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); mCPBA(meta-chloroperbenzoic acid; EDC (ethylcarbodiimide hydrochloride); BOC(tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl); DCC(dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl); Ac (acetyl); atm(atmosphere); TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS(triisopropylsilyl); TBS (t-butyldimethylsilyl); DMAP(4-dimethylaminopyridine); BSA (bovine serum albumin) ATP (adenosinetriphosphate); HRP (horseradish peroxidase); DMEM (Dulbecco's modifiedEagle medium); HPLC (high pressure liquid chromatography); BOP(bis(2-oxo-3-oxazolidinyl)phosphinic chloride); TBAF(tetra-n-butylammonium fluoride); HBTU(O-Benzotriazole-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate).HEPES (4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid); DPPA(diphenylphosphoryl azide); fHNO₃ (fumed HNO₃); and EDTA(ethylenediaminetetraacetic acid).

All references to ether are to diethyl ether; brine refers to asaturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionsare conducted under an inert atmosphere at room temperature unlessotherwise noted.

¹H NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, aVarian Unity-400 instrument, a Brucker AVANCE-400, or a General ElectricQE-300. Chemical shifts are expressed in parts per million (ppm, δunits). Coupling constants are in units of hertz (Hz). Splittingpatterns describe apparent multiplicities and are designated as s(singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m(multiplet), br (broad).

HPLC were recorded on a Gilson HPLC or Shimazu HPLC system by thefollowing conditions. Column: 50×4.6 mm (id) stainless steel packed with51 μm Phenomenex Luna C-18; Flow rate: 2.0 ml/min; Mobile phase: Aphase=50 mM ammonium acetate (pH 7.4), B phase=acetonitrile, 0–0.5 min(A: 100%, B: 0%), 0.5–3.0 min (A: 100–0%, B: 0–100%), 3.0–3.5 min (A:0%, B: 100%), 3.5–3.7 min (A: 0–100%, B: 100–0%), 3.7–4.5 min (A: 100%,B: 0%); Detection : UV 254 nm; Injection volume: 3 μL.

Low-resolution mass spectra (MS) were recorded on a JOEL JMS-AX505HA,JOEL SX-102, or a SCIEX-APliii spectrometer; LC-MS were recorded on amicromass 2 MD and Waters 2690; high resolution MS were obtained using aJOEL SX-102A spectrometer. All mass spectra were taken underelectrospray ionization (ESI), chemical ionization (Cl), electron impact(EI) or by fast atom bombardment (FAB) methods. Infrared (IR) spectrawere obtained on a Nicolet 510 FT-IR spectrometer using a 1-mm NaClcell. Most of the reactions were monitored by thin-layer chromatographyon 0.25 mm E. Merck silica gel plates (60F-254), visualized with UVlight, 5% ethanolic phosphomolybdic acid or p-anisaldehyde solution.Flash column chromatography was performed on silica gel (230–400 mesh,Merck).

Example 1 4-Amino-3-(4-methoxyphenyl)-2-(3-(methylsulfonylamino)phenyl)furo[2,3-d]pyrimidine

Example 1 was prepared according to procedures similar to those shown inScheme 2.

1(A) 2-Amino-3-cyano-4-(4-methoxyphenyl)furan

To a cooled solution of 2-hydroxy-4′-methoxyacetophenone (379 mg, 2.28mmol) in DMF (0.75 ml) was added malononitrile (166 mg, 2.51 mmol)followed by diethylamine (0.1 ml, 0.97 mmol). The mixture was stirred atroom temperature for 2 hours, and then poured into large amount of coldwater. The precipitate was filtrated, washed with water, and dried underreduced pressure to give the intermediate of Example 1(A) (424 mg, 87%)as a brown solid. 1H NMR (400 MHz, CDCl3) ppm 3.83 (s, 3H), 4.73 (brs,2H), 6.93 (m, 2H), 6.94 (s, 1H), 7.49 (m, 2H). LC/MS: m/z 215 (M+1)⁺.

1(B) 4-Amino-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine (Example 11)

A solution of the intemediate of Example 1(A) (409 mg, 1.91 mmol) informamide (12 ml) was refluxed (heated in an oil bath at around 200° C.)for 30 min. The mixture was cooled to room temperature, chilled in anice bath, and then poured into cold water. The precipitate wasfiltrated, washed with water, and dried under reduced pressure to givethe Intermediate of Example 1(B) (340 mg, 74%) as a brown solid. 1H NMR(400 MHz, CDCl3) ppm 3.89 (s, 3H), 5.17 (brs, 2H), 7.04 (m, 2H), 7.42(m, 2H), 7.47 (s, 1H), 8.40 (s, 1H). LC/MS: m/z 242 (M+1)⁺.

1(C) 4-Amino-2-bromo-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

To a suspension of the Intermediate of Example 1(B) (833 mg, 3.45 mmol)in carbon tetrachloride (10 ml) was added NBS (685 mg, 3.85 mmol). Afterstirring at room temperature for 0.5 hour, the resultant suspension wasconcentrated in vacuo, and then the residue was triturated with amixture of ethyl acetate and water. The insoluble material was filteredoff, and then the filtrate was extracted with ethyl acetate. The organicphase was passed through a small silica gel pad and concentrated invacuo. The residue was triturated with ethyl acetate/ether, filtrated,and dried under reduced pressure to give the Intermediate of Example1(C) (550 mg). 1H NMR (400 MHz, CDCl3) ppm 3.87 (s, 3H), 5.15 (brs, 2H),7.05 (m, 2H), 7.42 (m, 2H), 8.33 (s, 1H). LC/MS: m/z 320 (M)⁺, 322(M+2)⁺.

1(D) 4-Amino-3-(4-methoxyphenyl)-2-(3-(methylsulfonylamino)phenyl)furo[2,3-d]pyrimidine

To a mixture of the Intermediate of Example 1(C) (51 mg, 0.16 mmol),3-(methylsulfonyl-amino)phenylboronic acid, pinacol ester (55 mg, 0.19mmol), and tetra-kis(triphenylphosphine)palladium(O) (10.5 mg, 0.01mmol) was added DME (1.5 ml) and 2 M aqueous Na₂CO₃ (0.5 ml) under argonatmosphere. The mixture was heated at 85° C. for 12 hours. The mixturewas diluted with dichloromethane and the insoluble material was filteredoff. The filtrate was washed with water and purified by chromatographyon a silical gel column using hexane/ethyl acetate as an eluant toafford the title compound of Example 1(32 mg) as a solid. 1H NMR (400MHz, CDCl3) ppm 2.94 (s, 3H), 3.91 (s, 3H), 4.93 (brs, 2H), 6.26 (brs,1H), 7.08 (m, 2H), 7.18 (m, 1H), 7.31 (m, 2H), 7.40 (m, 3H), 8.39 (s,1H). LC/MS: m/z 411 (M+1)⁺, 409 (M−1)⁻.

Example 24-Amino-3-(4-(dimethylamino)phenyl)-2-(4-methoxyphenyl)-furo[2,3-d]pyrimidine

Example 2 was prepared according to procedures similar to those shown inScheme 3.

2(A) 2-Amino-3-cyano-5-(4-methoxyphenyl)furan

To a suspension of α-((4-methoxybenzoyl)methyl)malononitrile (9.66 g,45.1 mmol) in acetic acid (50 ml) was added conc. hydrogen chloride(11,3 ml). The mixture was stirred at room temperature for 2 hours, andthen poured into water. The resultant precipitation was filtrated,washed with water and ethanol, and dried under reduced pressure to givethe Intermediate of Example 2(A) (5.54 g, 56%) as a solid. 1H NMR (400MHz, CDCl3) ppm 3.83 (s, 3H), 4.74 (brs, 2H), 6.39 (s, 1H), 6.90 (m,2H), 7.42 (m, 2H).

2(B) 4-Amino-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine (Example 14)

A solution of the Intermediate of Example 2(A) (5.54 g, 25.9 mmol) informamide (100 ml) was heated at 200° C. for 1 hour. The mixture wascooled with an ice bath, and then poured into cold water. Theprecipitated material was filtrated, washed with water and ethanol, anddried under reduced pressure to give the Intermediate of Example 2(B)(5.61 g, 690%) as a solid. 1H NMR (400 MHz, CDCl3) ppm 3.87 (s, 3H),5.14 (s, 2H), 6.72 (s, 1H), 6.99 (m, 1H), 7.78 (m, 2H), 8.38 (s, 1H).LC/MS: m/z 242 (M+1)⁺;

2(C) 4-Amino-3-bromo-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine (Example33)

To a suspension of the Intermediate of Example 2(B) (4.02 g, 16.7 mmol)in carbon tetrachloride (100 ml), NBS (3.42 g, 19.2 mmol) was added. Themixture was refluxed for 4 hours, and then concentrated in vacuo. Theresidual material was suspended in ethanol, refluxed for 20 minutes, andcooled to 0° C. The precipitated material was filtrated, washed withethanol, and dried under reduced pressure to afford the Intermediate ofExample 2(C) (4.71 g, 88%). 1H NMR (400 MHz, DMSO-d6) ppm 3.84 (s, 3H),7.13 (m, 2H), 7.95 (m, 2H), 8.24 (s, 1H). LC/MS: m/z 320 (M)⁺, 322(M+2)⁺.

2(D)4-Amino-3-(4-(dimethylamino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

A mixture of the Intermediate of Example 2(C) (62.4 mg, 0.195 mmol),(4-dimethyl amino)phenyl-boronic acid (101 mg, 0.61 mmol),tetrakis(triphenyl phosphine)-palladium(O) (15.5 mg, 0.013 mmol) wassuspended in the mixture of DME (2.0 ml), DMF (0.5 ml), and 2 MaqueousNa₂CO₃ (1.0 ml) under argon atmosphere. The mixture was refluxedover night, diluted with dichloromethane, and washed with aqueousNa₂CO₃. The organic phase was separated, concentrated in vacuo, andpurified by chromatography on a silica gel column using hexane/ethylacetate (3:1-1:1) as an eluant to afford the title compound of Example 2(37 mg) as a solid. 1H NMR (400 MHz, CDCl3) ppm 3.05 (s, 6H), 3.80 (s,3H), 4.94 (brs, 2H), 6.82 (m, 4H), 7.31 (m, 2H), 7.56 (m, 2H), 8.34 (s,1H). LC/MS: m/z 361 (M+1)⁺.

Example 34-Amino-3-(4-((3-chlorophenyl)sulfonylamino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 3 was prepared according to procedures similar to those shown inScheme 3.

3(A) 4-Amino-3-(4-aminophenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine)

A mixture of the intermediate of Example 2(C) (628 mg),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(644 mg),tetrakis(triphenylphosphine)palla-dium(O) (226 mg) and 2 M Na₂CO₃ (4.9ml) in DME (20 ml) was heated at 80 ° C. and stirred for 15 hours. Thereaction mixture was poured into the mixture of ethyl acetate and satNH₄Cl. The resultant insoluble material was collected by filtration,which was purified by a SCX column (Varian, 10 g) to give theIntermediate of Example 3(A) (200 mg). 1H-NMR (400 MHz, DMSO-d6) ppm3.75 (s, 3H), 6.71 (d, J=8.3Hz, 2H), 6.94 (d, J=8.8 Hz, 2H), 7.11 (d,J=8.3 Hz, 2H), 7.45 (d, J=8.9 Hz, 2H), 8.21 (s, 1H). LC/MS: m/z 333(M+1)⁺.

3(B)4-Amino-3-(4-((3-chlorophenyl)sulfonylamino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

To a solution of the Intermediate of Example 3(A) (23.4 mg) in CH₂Cl₂(2ml) and pyridine (0.5 ml) was added m-chlorobenzensulfonyl chloride (155ul) at 0° C. The reaction mixture was stirred at ambient temperature afor 2 hours, and then poured into a mixture of AcOEt and 1N HCl. Theorganic layer was separated, dried over Na₂SO₄, and concentrated invacuo. The residue was purified by chromatography on a silica gel columnto give the title compound of Example 3 (28.5 mg). 1H NMR (400 MHz,DMSO-d6) ppm 3.76 (s, 3H), 6.86 (d, J=9.1 Hz, 2H), 7.24 (d, J=8.3 Hz,2H), 7.25 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.63 (d, J=7.8 Hz,1H), 7.73 (d, J=7.8 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.78 (s, 1H), 8.22(s, 1H). LC/MS: m/z 507 (M+1)⁺, 509 (M+3)⁺, 505 (M−1)⁻, 507 (M+1)⁻.

Example 44-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)amino-carbonylamino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 4 was prepared according to procedures similar to those shown inScheme 3.

To a solution of the Intermediate of Example 3(A) (28.8 mg) in DMF(2 ml)was added 2-fluoro-5-(trifluoromethyl)phenylisocyanate (13.8 ul). Thereaction mixture was stirred for 2 hours at room temperature, and thenconcentrated under reduced pressure. The residue was purified bypreparative TLC to give the title compound of Example 4 (27.7 mg). 1HNMR (400 MHz, DMSO-d6) ppm 3.75 (s, 3H), 6.95 (d, J=9.1 Hz, 2H), 7.41(d, J=9.1 Hz, 2H), 7.43 (d, J=8.8 Hz, 2H), 7.53 (dd, J=8.8 Hz, 10.9 Hz,1H), 7.66 (d, J=8.6 Hz, 2H), 8.64 (d, J=7.1 Hz, 1H), 9.04 (s, 1H), 9.46(s, 1H). LC/MS: m/z 538 (M+1)⁺, 536 (M−1)⁻.

Example 54-Amino-3-(4-(2,3-difluorophenyl)phenyl)-2-(3-sulfamoylphenyl)-furo[2,3-d]pyrimidine

Example 5 was prepared according to procedures similar to those shown inScheme 2.

5(A) 4-Amino-3-(4-bromophenyl)furo[2,3-d]pyrimidine

A suspension of 2-Amino-4-(4-bromophenyl)-3-cyanofuran in formamide wastreated by the same method as in the procedure of Example 1(B) to affordthe Intermediate of Example 5(A). 1H NMR (400 MHz, CDCl3) ppm 5.20 (brs,2H), 7.38 (m, 2H), 7.53 (s, 1H), 7.65 (m, 2H), 8.42 (s, 1H). LC/MS: m/z290 (M)⁺, 292 (M+2)⁺.

5(B) 4-Amino-3-(4-(2,3-difluorophenyl)phenyl)furo[2,3-d]pyrimidine

DME (5 ml) and 2 M Na₂CO₃ (1 ml) were added sequentially to a degassedmixture of the Intermediate of Example 5(A) (0.5 mmol, 145 mg),2,3-difluoro phenylboronic acid (0.75 mmol, 118.5 mg), andtetrakis-(triphenyl phosphine) palladium(0) (0.05 mmol, 57.8 mg). Theresultant suspension was heated at 80° C. under argon for 12 hours, andthen cooled down to room temperature. The mixture was extracted withethyl acetate 3 times (3×20 ml). The solvent was evaporated to drynessand the residual material was purified by chromatography on a SCX columnusing MeOH as an eluant to give the Intermediate of Example 5(B) (0.475mmol, 153.5 mg), which was used in the next step without furtherpurification.

1H-NMR(400 MHz, DMSO-d6) ppm 6.65 (br, 1H), 7.32–7.37 (m, 1H), 7.41–7.52(m, 2H), 7.66 (d, 2H, J=8.3 Hz), 7.74 (dd, 2H, J=1.5, 8.3 Hz), 8.08 (s,1H), 8.28 (s, 1H). LC/MS: m/z 324 (M+1)⁺.

5(C)4-Amino-2-bromo-3-(4-(2,3-difluorophenyl)phenyl)furo[2,3-d]-pyrimidine

The Intermediate of Example 5(B) was brominated by a similar method asfor the Intermediate of Example 1(C) except that THF was used as thesolvent to afford the Intermediate of Example 5(C). 1H-NMR(400 MHz,DMSO-d6) ppm 7.35–7.38 (m, 1H), 7.45–7.51 (m, 2H), 7.65 (d, 2H, J=8.1Hz), 7.78 (dd, 2H, J=1.3, 8.1 Hz), 8.27 (s, 1H). LC/MS: m/z 402 (M)⁺,404 (M+2)⁺.

5(D)4-Amino-3-(4-(2,3-difluorophenyl)phenyl)-2-(3-sulfamoyl-phenyl)furo[2,3-d]pyrimidine

The Intermediate of Example 5(C) was reacted with3-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)sulfamoylbenzen usingthe procedure of Example 5(B) to give the title compound of Example 5(80% after purification). 1H-NMR (400 MHz, DMSO-d6) ppm 7.36–7.39 (m,1H), 7.45–7.54 (m, 4H), 7.66 (d, 2H, J=8.3 Hz), 7.76 (dt, 1H, J=1.5, 7.6Hz), 7.81(dd, 2H, J=1.3, 8.3 Hz), 8.10 (t, 1H, J=1.2 Hz), 8.33 (s, 1H).LC/MS: m/z 479 (M+1)⁺.

Example 64-Amino-3-(4-(3-biphenyl)phenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine

Example 6 was prepared according to procedures similar to those shown inScheme 2.

6(A) 4-Amino-3-(4-(3-biphenyl)phenyl)furo[2,3-d]pyrimidine

The Intermediate of Example 5(A) (174 mg), (3-biphenyl)boronic acid (178mg), tetrakis-(triphenylphosphine)palladium(0) (69 mg), and K₃PO₄ (255mg) was suspended in DMF (7 ml) and water (1.7 ml). The mixture washeated at 80° C. and stirred overnight. The reaction mixture was pouredinto a mixture of ethyl acetate and sat. NH₄Cl. The resultant insolublematerial was filtered off and the filtrate was extracted with ethylacetate. The organic layer was separated, dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by chromatogphy on asilica gel column. The material was washed with ethanol and dried underreduced pressure to give the Intermediate of Example 6(A) (90 mg).1H-NMR (400 MHz, DMSO-d6) ppm 7.41 (m, 1H), 7.51 (m, 2H), 7.60–7.66 (m,3H), 7.69 (m, 1H), 7.75 (m, 1H), 7.79 (m, 2H), 7.95–7.99 (m, 3H), 8.07(s, 1H), 8.28 (s, 1H).

6(B) 4-Amino-2-bromo-3-(4-(3-biphenyl)phenyl)furo[2,3-d]pyrimidine

To a suspension of the Intermediate of Example 6(A) (72.4 mg) in amixture of carbon tetrachloride (10 ml) and ethyl acetate (15 ml) wasadded NBS (40.8 mg). The mixture was stirred at room temperature for 3hours. The reaction mixture was quenched by 10% Na₂S₂O₄ and extractedwith ethyl acetate. The organic layer was dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The residual solid was washedwith AcOEt-hexane to give the Intermediate of Example 6(B) (73.8 mg). 1HNMR (400 MHz, DMSO-d6) ppm 7.39–7.43 (m, 1H), 7.49–7.53 (m, 2H),7.59–7.64 (m, 3H), 7.7–7.72 (m, 1H), 7.76–7.82 (m, 3H), 8.01–7.97 (m,3H), 8.27 (s, 1H), 8.31 (s, 1H). LC/MS: m/z 442 (M)⁺, 444 (M+2)⁺.

6(C) 4-Amino-3-(4-(3-biphenyl)phenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine

The mixture of the Intermediate of Example 6(B) (40 mg),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)sulfamoylbenzene (38.2mg), tetrakis (triphenylphosphine)-palladium(O) (10.4 mg) and 2 M Na₂CO₃(0.23 ml) in DME (2.5 ml) was stirred at 80° C. for 15 hours. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by chromatography on a silica gel column and sequentiallypurified by a SCX column (Varian, 1 g) to remove triphenylphosphineoxideto give the title compound of Example 6 (7.1 mg). 1H NMR (400 MHz,DMSO-d6) ppm 7.39–7.43 (m, 1H), 7.47–7.54 (m, 5H), 7.6–7.66 (m, 3H),7.71–7.82 (m, 5H), 8.01–8.04 (m, 3H), 8.14 (s, 1H), 8.33 (s, 1H). LC/MS:m/z 519 (M+1)⁺, 517 (M−1)⁻.

Example 74-Amino-3-(4-biphenyl)-2-(4-fluoro-3-(methylsulfonylamino)-phenyl)furo[2,3-d]pyrimidine

Example 7 was prepared according to procedures similar to those shown inScheme 2.

7(A) 2-Amino-3-cyano-4-(4-biphenyl)furan

(2-hydroxy-4′-phenyl)acetophenone was reacted with malononitrile usingthe same procedure as in Example 1(A) to afford the Intermediate ofExample 7(A). 1H NMR (400 MHz, CDCl3) ppm 4.81 (brs, 2H), 7.07 (s, 1H),7.37 (m, 1H), 7.46 (m, 2H), 7.61–7.64 (m, 6H).

7(B) 4-Amino-3-(4-biphenyl)furo[2,3-d]pyrimidine

The Intermediate of Example 7(A) was treated with formamide using thesame procedure method as in Example 1(B) to afford the Intermediate ofExample 7(B). 1H NMR (400 MHz, CDCl3) ppm 5.25 (brs, 2H), 7.4–7.8 (m,10H), 8.43 (s, 1H). LC/MS: m/z 288 (M+1)⁺.

7(C) 4-Amino-3-(4-biphenyl)-2-bromofuro[2,3-d]pyrimidine

The Intermediate of Example 7B was brominated using the same procedureas in Example 1(C) except that a mixture of carbon tetrachloride andethyl acetate was used as a solvent to afford the Intermediate ofExample 7(C). 1H NMR (400 MHz, CDCl3) ppm 5.23 (brs, 2H), 7.42 (m, 1H),7.50 (m, 2H), 7.59 (m, 2H), 7.65 (m, 2H), 7.77 (m, 2H), 8.38 (s, 1H).LC/MS: m/z 366 (M)⁺, 368 (M+2)⁺.

7(D)4-Amino-3-(4-biphenyl)-2-(4-fluoro-3-(methylsulfonylamino)-phenyl)furo[2,3-d]pyrimidine

The Intermediate of Example 7(C) was reacted with2-(methylsulfonylamino)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)fluorobenzenusing the same method as in Example 1(D) to afford the title compound ofExample 7. 1H NMR (400 MHz, CDCl3) ppm 2.84 (s, 3H), 4.98 (brs, 2H),6.48 (brs, 1H), 7.12 (m, 1H), 7.41–7.53 (m, 4H), 7.58 (m, 2H), 7.66 (m,3H), 7.79 (m, 2H), 8.42 (s, 1H). LC/MS: m/z 475 (M+1)⁺, 473 (M−1)⁻.

Example 84-Amino-2-(3-cyanophenyl)-3-(4-((2-fluoro-5-(trifluoromethyl)-phenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 8 was prepared according to procedures similar to those shown inScheme 2.

8(A) 3-(4-Acetamidephenyl)-4-aminofuro[2,3-d]pyrimidine

The title Intermediate of Example 8(A) was obtained using proceduressimilar to those of Example 1(B).

1H NMR (400 MHz, CDCl3) ppm 2.24 (s, 3H), 5.17 (brs, 2H), 7.46 (d, 2H,J=8.3 Hz), 7.50 (s, 1H), 7.66 (d, 2H, J=8.3 Hz), 8.41 (s, 1H). LC/MS:m/z 269 (M+1)⁺.

8(B) 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine

The Intermediate of Example 8(A) (242 mg, 0.90 mmol) was suspended in 2M KOH in ethanol/H₂O (4:1, 20 ml). The mixture was stirred at 60° C.overnight, and then concentrated in vacuo. The residual oil wastriturated with water (6 ml). The precipitated material was filtrated,washed with water, and dried under reduced pressure to give theIntermediate of Example 8(B) (118 mg, 58%) as an orange powder. 1H NMR(400 MHz, CDCl3) ppm 3.85 (brs, 2H), 5.18 (brs, 2H), 6.79 (d, 2H, J=8.4Hz), 7.28 (d, 2H, J=8.4 Hz), 7.44 (s, 1H), 8.39 (s, 1H). 1H NMR (400MHz, DMSO-d6) ppm 5.35 (s, 2H), 6.68 (d, J=8.6 Hz, 2H), 7.16 (d, J=8.3Hz, 2H), 7.78 (s, 1H), 8.22 (s, 1H). LC/MS: m/z 227 (M+1)⁺.

8(C)4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine (Example 232)

To a solution of the Intermediate of Example 8(B) (80 mg) in THF (10 ml)was added 2-fluoro-5-(trifluoromethyl)phenylisocyanate (53.8 ul) and thereaction mixture was stirred at 0° C. for 2 hours. The solvent wasremoved under reduced pressure and the residue was purified bychromatography on a silica gel column to afford the Intermediate ofExample 8(C) (117 mg). 1H NMR (400 MHz, DMSO-d6) ppm 7.39–7.42 (m, 1H),7.47 (d, J=8.6 Hz, 2H), 7.49–7.54 (m, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.95(s, 1H), 8.26 (s, 1H), 8.63 (d, J=7.1 Hz, 1H), 8.99 (s, 1H), 9.39 (s,1H). LC/MS: m/z 432 (M+1)⁺, 430 (M−1)⁻.

8(D)4-Amino-2-bromo-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine(Example 272)

The Intermediate of Example 8(C) (218 mg) was brominated using the sameprocedure as in Example 1(C) except that a mixture of carbontetrachloride (15 ml) and ethyl acetate (30 ml) was used as a solvent toafford the Intermediate of Example 8(D) (222 mg). 1H NMR (400 MHz,DMSO-d6) ppm 7.40–7.43 (m, 1H), 7.45 (d, J=8.6 Hz, 2H), 7.52 (dd, J=8.8Hz, 10.9 Hz, 1H), 7.66 (d, J=8.6 Hz, 2H), 8.24 (s, 1H), 8.64 (d, J=7.1Hz), 9.0 (s, 1H), 9.41 (s, 1H). LC/MS: m/z 510 (M)⁺, 512 (M+2)⁺.

8(E)4-Amino-2-(3-cyanophenyl)-3-(4-((2-fluoro-5-(trifluoromethyl)-phenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

The Intermediate of Example 8D (40 mg) was reacted with(3-cyanophenyl)boronic acid (34.4 mg) using the same procedure as inExample 1(D) to afford the title compound of Example 8 (40.5 mg). 1H NMR(400 MHz, DMSO-d6) ppm 7.4–7.44 (m, 1H), 7.47 (d, J=8.6 Hz, 2H),7.50–7.61 (m, 2H), 7.69–7.73 (m, 3H), 7.80 (d, J=7.8 Hz, 2H), 7.83 (s,1H), 8.30 (s, 1H), 8.63 (d, J=7.3 Hz, 1H), 9.06 (s, 1H), 9.51 (s, 1H).LC/MS: m/z 533 (M+1)⁺, 531 (M−1)⁻.

The following Examples 9–275 were prepared according according toprocedures similar to those shown in similarly to Scheme 1, Scheme 2,Scheme 3, or Scheme 4 and obtained according to similar methods asrecited in Examples 1–8.

Example 9 4-Amino-2,3-diphenylfuro[2,3-d]pyrimidine

Example 9 was prepared according to procedures similar to those shown inScheme 1.

HPLC: RT 3.06 min, LC/MS: m/z 288 (M+1)⁺.

Example 10 4-Amino-2,3-bis(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 10 was prepared according to procedures similar to those shownin Scheme 2.

1HNMR (400 MHz, CDCl3) ppm 3.80 (s, 3H), 3.90 (s, 3H), 4.89(brs, 2H),6.82 (d, J=8.9 Hz, 2H), 7.05 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.7 Hz, 2H),7.50 (d, J=9.0 Hz, 2H), 8.36 (s, 1H); HPLC: RT 3.04 min, LC/MS: m/z 348(M+1)⁺.

Example 11 (Example 1(B)) 4-Amino-3-(methoxyphenyl)furo[2,3-d]pyrimidine

1H NMR (400 MHz, CDCl3) ppm 3.89 (s, 3H), 5.17 (brs, 2H), 7.04 (m, 2H),7.42 (m, 2H), 7.47 (s, 1H), 8.40 (s, 1H); HPLC: RT 2.60 min, LC/MS: m/z242 (M+1)⁺.

Example 124-Amino-2,3-bis(3,4-O-methylidenedioxyphenyl)furo[2,3-d]pyrimidine

Example 12 was prepared according to procedures similar to those shownin Scheme 1.

1H NMR (400 Hz, CDCl3) ppm 4.94 (s, 2H), 5.97 (s, 2H), 6.09 (s, 2H),6.76 (d, J=8.2 Hz, 1H), 6.91–7.02 (m, 4H), 7.14 (dd, J=1.7, 8.2 Hz, 1H),8.36 (s, 1H); HPLC: RT 2.93 min, LC/MS: m/z 376 (M+1)⁺.

Example 13 4-Amino-2,3-dibutylfuro[2,3-d]pyrimidine

Example 13 was prepared according to procedures similar to those shownin Scheme 1.

HPLC: RT 3.23 min, LC/MS: m/z 248 (M+1)⁺.

Example 14: (Example 2(8))4-Amino-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

HPLC: RT 2.59 min, LC/MS: m/z 242 (M+1)⁺.

Example 15 4-Amino-2-(3-furanyl)-3-(2-furanyl)furo[2,3-d]pyrimidine

Example 15 was prepared according to procedures similar to those shownin Scheme 1.

1H NMR (400 MHz, CDCl3) ppm 5.93 (brs, 2H), 6.57 (m, 1H), 6.63 (m, 1H),6.97 (d, J=3.4 Hz, 1H), 7.00 (d, J=3.4 Hz, 1H), 7.54 (m, 1H), 7.62 (m,1H), 8.38 (s, 1H); HPLC: RT min, LC/MS: m/z 268 (M+1)⁺.

Example 16 4-Amino-2,3-bis(4-methylphenyl)furo[2,3-d]pyrimidine

Example 16 was prepared according to procedures similar to those shownin Scheme 1.

1H NMR (400 MHz, CDCl3) ppm 2.33 (s, 3H), 2.46 (s, 3H), 4.89 (brs, 2H),7.10 (m, 2H), 7.32 (m, 2H), 7.38 (m, 2H), 7.45 (m, 2H), 8.37 (s, 1H);HPLC: RT min. LC/MS: m/z 316 (M+1)⁺.

Example 17 4-Amino-2-(4-methylphenyl)-3-(4-trifluoromethylphenyl)furo[2,3-d]pyrimidine

Example 17 was prepared according to procedures similar to those shownin Example 2.

1HNMR (400 MHz, CDCl3) ppm 3.81 (s, 3H), 4.84 (brs, 2H), 6.85 (d, J=8.9Hz, 2H), 7.43 (d, J=9.0 Hz, 2H), 7.65 (d, J=7.9 Hz, 2H), 7.80 (d, J=8.1Hz, 2H), 8.40 (s, 1H); HPLC: RT 3.27 min, LC/MS: m/z 386 (M+1)⁺.

Example 18 4-Amino-3-(4-methylphenyl)-2-(4-trifluoromethylphenyl)furo[2,3-d]pyrimidine

Example 18 was prepared according to procedures similar to those shownin Example 1.

1HNMR (400 MHz, CDCl3) ppm 3.90 (s, 3H), 4.96 (brs, 2H), 7.07 (d, J=8.7Hz, 2H), 7.40 (d, J=8.6 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.4Hz, 2H), 8.40 (s, 1H); HPLC: RT 3.34 min, LC/MS: m/z 386 (M+1)⁺.

Example 194-Amino-2-(2-benzothienyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 19 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 Hz, CDCl3) ppm 3.94 (s, 3H), 4.95 (s, 2H), 7.12 (d, J=8.6Hz, 2H), 7.29–7.33 (m, 2H), 7.49 (d, J=8.6 Hz, 2H), 7.64 (s, 1H), 7.70(d, J=7.7 Hz, 1H), 7.74 (d, J=7.3 Hz, 1H), 8.40 (s, 1H); HPLC: RT 3.37min, LC/MS: m/z 374 (M+1)⁺.

Example 204-Amino-2-(4-biphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 20 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, CDCl3) ppm 3.92 (s, 3H), 4.92 (brs, 2H), 7.08 (m, 2H),7.35 (m, 1H), 7.42–7.46 (m, 4H), 7.54 (m, 2H), 7.58 (m, 2H), 7.64 (m,2H), 8.40 (s, 1H); HPLC: RT 3.57 min, LC/MS: m/z 394 (M+1)⁺.

Example 214-Amino-2-(2-chlorophenyl)-3-(4-methoxylphenyl)furo[2,3-d]pyrimidine

Example 21 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 Hz, CDCl3) ppm 3.91 (s, 3H), 4.93 (s, 2H), 7.08 (d, J=8.6Hz, 2H), 7.20–7.24 (m, 2H), 7.38–7.42 (m, 3H), 7.61 (s, 1H), 8.40 (s,1H); HPLC: RT 3.28 min, LC/MS: m/z 352 (M+1)⁺.

Example 224-Amino-2-(2-methoxylphenyl)-3-(4-methoxylphenyl)furo[2,3-d]pyrimidine

Example 22 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, CDCl3) ppm 3.46 (s, 3H), 3.83 (s, 3H), 5.07 (brs, 2H),6.85 (m, 1H), 6.84–6.99 (m, 3H), 7.27–7.29 (m, 2H), 7.34 (m, 1H), 7.48(m, 1H), 8.39 (s, 1H); HPLC: RT 2.92 min, LC/MS: m/z 348 (M+1)⁺.

Example 234-Amino-3-(4-methoxyphenyl)-2-(1-naphthyl)furo[2,3-d]pyrimidine

Example 23 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, CDCl3) ppm 3.77 (s, 3H), 5.12 (brs, 2H), 6.85 (m, 2H),7.24 (m, 2H), 7.35–7.51 (m, 4H), 7.87 (m, 2H), 8.00 (m, 1H), 8.45 (s,1H); HPLC: RT 3.15 min, LC/MS: m/z 368 (M+1)⁺.

Example 244-Amino-3-(4-methoxyphenyl)-2-(2-naphthyl)furo[2,3-d]pyrimidine

Example 24 was prepared according to procedures similar to those shownin Example 1.

1HNMR (400 MHz, CDCl3) ppm 3.91 (s, 3H), 4.93 (brs, 2H), 7.07 (d, J=8.7Hz, 2H), 7.44–7.47 (m, 4H), 7.50–7.52 (m, 1H), 7.69 (d, J=8.9 Hz, 1H),7.74–7.77 (m, 2H), 8.17 (s, 1H), 8.40 (s, 1H); HPLC: RT 2.60 min, LC/MS:m/z 368 (M+1)⁺.

Example 254-Amino-3-(4-methoxyphenyl)-2-(4-trifluoromethyloxyphenyl)-furo[2,3-d]pyrimidine

Example 25 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 Hz, CDCl3) ppm 3.90 (s, 3H), 4.91 (s, 2H), 7.06 (d, J=8.6Hz, 2H), 7.12 (d, J=8.9 Hz, 2H), 7.40 (d, J=8.6 Hz, 2H), 7.57 (d, J=8.9Hz, 2H), 8.38 (s, 1H); HPLC: RT 3.42 min, LC/MS: m/z 402 (M+1)⁺.

Example 264-Amino-2-(3-methoxyphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 26 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, CDCl3) ppm 3.69 (s, 3H), 3.88 (s, 3H), 4.89 (brs, 2H),6.82 (m, 1H), 7.05 (m, 2H), 7.11 (m, 1H), 7.16 (m, 2H), 7.41 (m, 2H),8.37 (s, 1H); HPLC: RT 3.03 min, LC/MS: m/z 348 (M+1)⁺.

Example 273-(3-Acetamidophenyl)-4-amino-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 27 was prepared according to procedures similar to those shownin Example 2.

1HNMR (400 MHz, CDCl3) ppm 2.20 (s, 3H), 3.81 (s, 3H), 6.83 (d, J=9.0Hz, 2H), 7.22–7.26 (m, 2H), 7.45–7.50 (m, 3H), 7.57 (m, 1H), 7.65 (m,1H), 8.37 (s, 1H); HPLC: RT 2.71 min, LC/MS: m/z 375 (M+1)⁺.

Example 284-Amino-3-(3,4-dimethoxyphenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 28 was prepared according to procedures similar to those shownin Example 2.

HPLC: RT 2.94 min, LC/MS: m/z 378 (M+1)⁺.

Example 294-Amino-2-(4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)furo[2,3-d]pyrimidine

Example 29 was prepared according to procedures similar to those shownin Example 2.

HPLC: RT 2.92 min, LC/MS: m/z 408 (M+1)⁺.

Example 304-Amino-3-(4-isopropylphenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 30 was prepared according to procedures similar to those shownin Example 2.

1H NMR (400 Hz, CDCl3) ppm 1.32 (d, J=7.0 Hz, 6H), 2.99 (m, 1H), 3.79(s, 3H), 4.87 (s, 2H), 6.81 (d, J=8.9 Hz, 2H), 7.34–7.40 (m, 4H), 7.48(d, J=8.9 Hz, 2H), 8.35 (s, 1H); HPLC: RT 3.48 min, LC/MS: m/z 360(M+1)⁺.

Example 314-Amino-3-(4-butylphenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 31 was prepared according to procedures similar to those shownin Example 2.

HPLC: RT 3.72 min, LC/MS: m/z 374 (M+1)⁺.

Example 324-Amino-2-(4-methoxyphenyl)-3-(3-methoxyphenyl)furo[2,3-d]pyrimidine

Example 32 was prepared according to procedures similar to those shownin Example 2.

1H NMR (400 MHz, CDCl3) ppm 3.81 (s, 3H), 3.83 (s, 3H), 4.91 (brs, 2H),6.83 (m, 2H), 7.02 (m, 2H), 7.08 (m, 1H), 7.45 (m, 1H), 7.51 (m, 2H),8.37 (s, 1H); HPLC: RT 3.07 min, LC/MS: m/z 348 (M+1)⁺.

Example 33: (Example 2(c))4-Amino-3-bromo-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

1H NMR (400 MHz, DMSO-d6) ppm 3.84 (s, 3H), 7.13 (m, 2H), 7.95 (m, 2H),8.24 (s, 1H); HPLC: RT 2.87 min, LC/MS: m/z 320 (M)⁺, 322 (M+2)⁺.

Example 344-Amino-3-(4-biphenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 34 was prepared according to procedures similar to those shownin Example 2.

1HNMR (400 MHz, CDCl3) ppm 3.80 (s, 3H), 4.94 (brs, 2H), 6.84 (d, J=9.1Hz, 2H), 7.39–7.43 (m, 1H), 7.49–7.59 (m, 6H), 7.69 (d, J=8.6 Hz, 2H),7.77 (d, J=8.3 Hz, 2H), 8.39 (s, 1H); HPLC: RT 3.55 min, LC/MS: m/z 394(M+1)⁺.

Example 354-Amino-2-(4-methoxyphenyl)-3-(2-methoxyphenyl)furo[2,3-d]pyrimidine

Example 35 was prepared according to procedures similar to those shownin Example 2.

HPLC: RT 3.01 min. LC/MS: m/z 348 (M+1)⁺.

Example 364-Amino-2-(4-methoxyphenyl)-3-((4-methylthio)phenyl)furo[2,3-d]pyrimidine

Example 36 was prepared according to procedures similar to those shownin Example 2.

1H NMR (400 Hz, CDCl3) ppm 2.57 (s, 3H), 3.81 (s, 3H), 4.92 (s, 2H),6.83 (d, J=9.1 Hz, 2H), 7.36–7.42 (m, 4H), 7.50 (d, J=8.8 Hz, 2H), 8.36(s, 1H); HPLC: RT 3.22 min, LC/MS: m/z 364 (M+1)⁺.

Example 374-Amino-2-(4-methoxyphenyl)-3-(1-naphthyl)furo[2,3-d]pyrimidine

Example 37 was prepared according to procedures similar to those shownin Example 2.

1H NMR (400 MHz, CDCl3) ppm 3.73 (s, 3H), 4.48 (brs, 2H), 6.71 (m, 2H),7.36 (m, 2H), 7.47 (m, 1H), 7.56–7.62 (m, 3H), 7.77 (m, 1H), 8.00–8.04(m, 2H), 8.39 (s, 1H); HPLC: RT 3.21 min, LC/MS: m/z 368 (M+1)⁺.

Example 384-Amino-2-(4-methoxyphenyl)-3-(2-naphthyl)furo[2,3-d]pyrimidine

Example 38 was prepared according to procedures similar to those shownin Example 2.

HPLC: RT 3.36 min, LC/MS: m/z 368 (M+1)⁺.

Example 394-Amino-2-(4-methoxyphenyl)-3-(4-(trifluoromethyloxy)phenyl)-furo[2,3-d]pyrimidine

Example 39 was prepared according to procedures similar to those shownin Example 2.

1HNMR (400 MHz, CDCl3) ppm 3.81 (s, 3H), 4.87 (brs, 2H), 6.84 (d, J=8.8Hz, 2H), 7.38 (d, J=7.8 Hz, 2H), 7.44 (d, J=8.8 Hz, 2H), 7.54 (d, J=8.6Hz, 2H), 8.38 (s, 1H); HPLC: RT 3.32 min, LC/MS: m/z 402 (M+1)⁺.

Example 404-Amino-3-(2,5-dimethoxyphenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 40 was prepared according to procedures similar to those shownin Example 2.

HPLC: RT 2.97 min, LC/MS: m/z 378 (M+1)⁺.

Example 414-Amino-2-(4-methoxyphenyl)-3-(4-(methylsulfonyl)phenyl)-furo[2,3-d]pyrimidine

Example 41 was prepared according to procedures similar to those shownin Example 2.

1H NMR (400 Hz, CDCl3) ppm 3.19 (s, 3H), 3.82 (s, 3H), 4.85 (s, 2H),6.85 (d, J=8.8 Hz, 2H), 7.42 (d, J=8.8 Hz, 2H), 7.73 (d, J=8.3 Hz, 2H),8.10 (d, J=8.3 Hz, 2H), 8.41 (s, 1H); HPLC: RT 2.77 min, LC/MS: m/z 396(M+1)⁺.

Example 424-Amino-2-(4-methoxyphenyl)-3-(4-(phenyloxy)phenyl)furo[2,3-d]pyrimidine

Example 42 was prepared according to procedures similar to those shownin Example 2.

1H NMR (400 MHz, CDCl3) ppm 3.82 (s, 3H), 4.91 (brs, 2H), 6.85 (m, 2H),7.13 (m, 4H), 7.20 (m, 1H), 7.43 (m, 4H), 7.51 (m, 2H), 8.39 (brs, 1H);HPLC: RT 3.50 min, LC/MS: m/z 410 (M+1)⁺.

Example 434-Amino-2-(4-methoxyphenyl)-3-(3-pyridyl)furo[2,3-d]pyrimidine

Example 43 was prepared according to procedures similar to those shownin Example 2.

1H NMR (400 MHz, CDCl3) ppm 3.81 (s, 3H), 4.81 (brs, 2H), 6.84 (m, 2H),7.42–7.50 (m, 3H), 7.84 (m, 1H), 8.40 (s, 1H), 8.76 (m, 1H), 8.79 (m,1H); HPLC: RT 2.72 min, LC/MS: m/z 319 (M+1)⁺.

Example 444-Amino-3-(4-cyanophenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 44 was prepared according to procedures similar to those shownin Example 2.

1HNMR (400 MHz, CDCl3) ppm 3.82 (s, 3H), 4.85 (brs, 2H), 6.85 (d, J=9.0Hz, 2H), 7.40 (d, J=9.0 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.83 (d, J=8.4Hz, 2H), 8.40 (s, 1H); HPLC: RT 3.11 min, LC/MS: m/z 343 (M+1)⁺.

Example 454-Amino-2-(4-methoxyphenyl)-3-(4-tert-butylphenyl)furo[2,3-d]pyrimidine

Example 45 was prepared according to procedures similar to those shownin Example 2.

HPLC: RT 3.75 min, LC/MS: m/z 374 (M+1)⁺.

Example 464-Amino-2-(4-methoxyphenyl)-3-((3-fluoro-4-phenyl)phenyl)-furo[2,3-d]pyrimidine

Example 46 was prepared according to procedures similar to those shownin Example 2.

1H NMR (400 Hz, CDCl3) ppm 3.82 (s, 3H), 4.96 (s, 2H), 6.87 (d, J=8.8Hz, 2H), 7.30–7.66 (m, 10H), 8.40 (s, 1H); HPLC: RT 3.63 min, LC/MS: m/z412 (M+1)⁺.

Example 474-Amino-3-((4-benzyloxy-3-fluoro)phenyl)-2-(4-methoxyphenyl)-furo[2,3-d]pyrimidine

Example 47 was prepared according to procedures similar to those shownin Example 2.

1H NMR (400 MHz, CDCl3) ppm 3.82 (s, 3H), 4.86 (brs, 2H), 5.23 (s, 2H),6.83 (m, 2H), 7.13–7.24(m, 3H), 7.37–7.52 (m, 7H), 8.37 (s, 1H); HPLC:RT 3.57 min, LC/MS: m/z 442 (M+1)⁺.

Example 484-Amino-3-((4-ethylthio)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 48 was prepared according to procedures similar to those shownin Example 2.

1H NMR (400 MHz, CDCl3) ppm 1.41 (t, 3H, J=7.3 Hz), 3.05 (q, 2H, J=7.3Hz), 3.81 (s, 3H), 4.89 (brs, 2H), 6.83 (m, 2H), 7.41 (m, 4H), 7.49 (m,2H), 7. (m, 2H), 8.37 (s, 1H); HPLC: RT 3.50 min, LC/MS: m/z 378 (M+1)⁺.

Example 494-Amino-3-(3-chloro-4-fluorophenyl)-2-(4-methoxyphenyl)-furo[2,3-d]pyrimidine

Example 49 was prepared according to procedures similar to those shownin Example 1.

1HNMR (400 MHz, CDCl3) ppm 3.91 (s, 3H), 4.94 (brs, 2H), 7.04 (dd, J=8.7Hz, 1H), 7.08 (d, J=8.8 Hz, 2H), 7.37 (ddd, J=2.3 Hz, 4.6 Hz, 8.7 Hz,1H), 7.39 (dd, J=8.6 Hz, 2H), 7.66 (dd, J=2.3 Hz, 7.1 Hz), 8.39 (s, 1H);HPLC: RT 3.50 min, LC/MS: m/z 370 (M+1)⁺, 372 (M+3)⁺.

Example 504-Amino-2-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 50 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.71 min, LC/MS: m/z 386 (M)⁺, 388(M+1)⁺.

Example 514-Amino-2-(4-methoxyphenyl)-3-(2-phenylethyn-1-yl)furo[2,3-d)pyrimidine

Example 51 was prepared according to procedures similar to those shownin Example 2.

1HNMR (400 MHz, CDCl3) ppm 3.88 (s, 3H), 5.66 (brs, 2H), 7.02 (d, J=9.1Hz, 2H), 7.42–7.45 (m, 3H), 7.57–7.60 (m, 2H), 8.21 (d, J=9.1 Hz, 2H),8.37 (s, 1H); HPLC: RT 3.61 min, LC/MS: m/z 342 (M+1)⁺.

Example 524-Amino-3-(4-methoxyphenyl)-2-(2-methylphenyl)furo[2,3-d]pyrimidine

Example 52 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.23 min, LC/MS: m/z 332 (M+1)⁺.

Example 534-Amino-2-(2-chlorophenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 53 was prepared according to procedures similar to those shownin Example 1.

1HNMR (400 MHz, CDCl3) ppm 3.82 (s, 3H), 5.14 (brs, 2H), 6.93 (d, J=8.8Hz, 2H), 7.21–7.28 (m, 3H), 7.33 (ddd, J=1.6 Hz, 7.7 Hz, 1H), 7.37 (dd,J=1.6 Hz, 7.7 Hz, 1H), 7.42 (dd, J=1.1 Hz, 8.0 Hz), 8.43 (s, 1H); HPLC:RT 3.22 min, LC/MS: m/z 352 (M+1)⁺, 354 (M+1)⁺.

Example 544-Amino-2-(2-fluorophenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 54 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.17 min, LC/MS: m/z 336 (M+1)⁺.

Example 554-Amino-2-(3-acetamidophenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 55 was prepared according to procedures similar to those shownin Example 1.

1HNMR (400 MHz, CDCl3) ppm 2.17 (s, 3H), 3.91 (s, 3H), 4.93 (brs, 2H),7.07 (d, J=8.8 Hz, 2H), 7.17–7.23 (m, 2H), 7.41 (d, J=8.6 Hz, 2H), 7.54(s, 1H), 7.70 (d, J=7.1 Hz, 1H), 8.38 (s, 1H); HPLC: RT 2.77 min, LC/MS:m/z 375 (M+1)⁺.

Example 564-Amino-3-(4-methoxyphenyl)-2-(3-pyridyl)furo[2,3-d]pyrimidine

Example 56 was prepared according to procedures similar to those shownin Example 1.

1HNMR (400 MHz, CDCl3) ppm 3.90 (s, 3H), 4.99 (brs, 2H), 7.07 (d, J=8.8Hz, 2H), 7.26 (dd, J=4.8 Hz, 8.3 Hz, 1H), 7.41 (d, J=8.6 Hz, 2H), 7.89(ddd, J=1.8 Hz, 8.1 Hz, 2H), 8.40 (s, 1H), 8.49 (dd, J=1.8 Hz, 4.8 Hz,1H), 8.75 (d, J=1.5 Hz, 1H); HPLC: RT 2.76 min, LC/MS: m/z 319 (M+1)⁺.

Example 574-Amino-3-(2-butylethyn-1-yl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 57 was prepared according to procedures similar to those shownin Example 2.

1HNMR (400 MHz, CDCl3) ppm 1.00 (t, J=7.2 Hz, 3H), 1.49–1.73 (m, 4H),2.58 (t, J=7.1 Hz, 2H), 3.88 (s, 3H), 5.63 (brs, 2H), 6.99 (d, J=9.1 Hz,2H), 8.15 (d, J=9.1 Hz, 2H), 8.34 (s, 1H); HPLC: RT 3.62 min, LC/MS: m/z322 (M+1)⁺.

Example 584-Amino-3-(2-(3-methylbutyl)ethyn-1-yl)-2-(4-methoxyphenyl)-furo[2,3-d]pyrimidine

Example 58 was prepared according to procedures similar to those shownin Example 2.

HPLC: RT 3.74 min, LC/MS: m/z 336 (M+1)⁺.

Example 594-Amino-3-(2-(tert-butyl)ethyn-1-yl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 59 was prepared according to procedures similar to those shownin Example 2.

HPLC: RT 3.59 min, LC/MS: m/z 322 (M+1)⁺.

Example 604-Amino-3-(4-(hydroxymethyl)phenyl)-2-(4-methoxyphenyl)-furo[2,3-d]pyrimidine

Example 60 was prepared according to procedures similar to those shownin Example 2.

1H NMR (400 Hz, CDCl3) ppm 1.84 (t, J=5.8 Hz, 1H), 3.80 (s, 3H), 4.83(d, J=5.8 Hz, 2H), 4.85 (s, 2H), 6.82 (d, J=9.1 Hz, 2H), 7.46–7.55 (m,6H), 8.37 (s, 1H); HPLC: RT 2.80 min, LC/MS: m/z 348 (M+1)⁺.

Example 614-Amino-3-(4-biphenyl)-2-(2-methoxyphenyl)furo[2,3-d]pyrimidine

Example 61 was prepared according to procedures similar to those shownin Example 2.

1H NMR (400 MHz, CDCl3) ppm 3.40 (s, 3H), 5.15 (brs, 2H), 6.84 (m, 1H),7.00 (m, 1H), 7.34–7.49 (m, 6H), 7.55 (m, 1H), 7.62–7.66 (m, 4H), 8.42(s, 1H); HPLC: RT 3.56 min, LC/MS: m/z 394 (M+1)⁺.

Example 62

4-Amino-2-(2-methoxyphenyl)-3-((4-methylthio)phenyl)furo[2,3-d]pyrimidine

Example 62 was prepared according to procedures similar to those shownin Example 2.

HPLC: RT 3.29 min, LC/MS: m/z 364 (M+1)⁺.

Example 634-Amino-3-(4-methoxyphenyl)-2-(2-phenylethyn-1-yl)furo[2,3-d]pyrimidine

Example 63 was prepared according to procedures similar to those shownin Example 1.

1HNMR (400 MHz, CDCl3) ppm 3.90 (s, 3H), 5.25 (brs, 2H), 7.09 (d, J=8.8Hz, 2H), 7.35–7.36 (m, 3H), 7.46–7.49 (m, 2H), 7.59 (d, J=8.6 Hz, 2H),8.43 (s, 1H); HPLC: RT 3.43 min, LC/MS: m/z 342 (M+1)⁺.

Example 644-Amino-2-(2-butylethyn-1-yl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 64 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.46 min, LC/MS: m/z 322 (M+1)⁺.

Example 654-Amino-2-(2-biphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 65 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.44 min, LC/MS: m/z 394 (M+1)⁺.

Example 664-Amino-2-(3-biphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 66 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.70 min, LC/MS: m/z 394 (M+1)⁺.

Example 674-Amino-2-(4-(2-carboxyethyl)phenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 67 was prepared according to procedures similar to those shownin Example 1.

1HNMR (400 MHz, CDCl3-MeOH-d4) ppm 2.61 (t, J=7.8 Hz, 2H), 2.92 (t,J=7.8 Hz, 2H), 3.91 (s, 3H), 7.06 (d, J=8.6 Hz, 2H), 7.14 (d, J=8.1 Hz,2H), 7.40 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.3 Hz, 2H), 8.31 (s, 1H); HPLC:RT 2.36 min, LC/MS: m/z 390 (M+1)⁺, 388 (M−1)⁻.

Example 684-Amino-3-(4-methoxyphenyl)-2-(4-(methylsulfonyl)phenyl)-furo[2,3-d]pyrimidine

Example 68 was prepared according to procedures similar to those shownin Example 1.

1HNMR (400 MHz, CDCl3) ppm 3.05 (s, 3H), 3.92 (s, 3H), 5.01 (brs, 2H),7.10 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.6 Hz, 2H), 7.74 (d, J=8.6 Hz, 2H),7.85 (d, J=8.8 Hz, 2H), 8.42 (s, 1H); HPLC: RT 2.84 min, LC/MS: m/z 396(M+1)⁺.

Example 694-Amino-2-(4-carboxyphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 69 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.26 min, LC/MS: m/z 362 (M+1)⁺, 360 (M−1)⁻.

Example 704-Amino-3-(4-methoxyphenyl)-2-(1-(4-chlorophenyl)-1-hydroxy)methyl)furo[2,3-d]pyrimidine

Example 70 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.01 min, LC/MS: m/z 382 (M+1)⁺, 384 (M+3)⁺.

Example 714-Amino-3-(4-isopropylphenyl)-2-(2-methoxyphenyl)furo[2,3-d]pyrimidine

Example 71 was prepared according to procedures similar to those shownin Example 2.

HPLC: RT 3.56 min, LC/MS: m/z 360 (M+1)⁺.

Example 724-Amino-3-(4-(cyclopentyloxy)phenyl)-2-(2-methoxyphenyl)furo[2,3-d]pyrimidine

Example 72 was prepared according to procedures similar to those shownin Example 2.

1H NMR (400 Hz, CDCl3) ppm 1.62–1.94 (m, 8H), 3.45 (s, 3H), 4.77 (m,1H), 5.10 (s, 2H), 6.85 (d, J=8.3 Hz, 1H), 6.89 (d, J=8.6 Hz, 2H), 6.97(dt, J=0.9 Hz, 7.5 Hz, 1H), 7.24 (d, J=8.8 Hz, 2H), 7.34 (ddd, J=1.5,7.3, 8.5 Hz, 1H), 7.48 (dd, J=1.8, 7.6 Hz, 1H), 8.38 (s, 1H); HPLC: RT3.64 min, LC/MS: m/z 402 (M+1)⁺.

Example 734-Amino-3-(4-(isopropyloxy)phenyl)-2-(2-methoxyphenyl)furo[2,3-d]pyrimidine

Example 73 was prepared according to procedures similar to those shownin Example 2.

HPLC: RT 3.39 min, LC/MS: m/z 376 (M+1)⁺.

Example 744-Benzyloxycarbonylamino-3-(4-methoxyphenyl)furo[2,3-d]-pyrimidine

Example 74 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, CDCl3) ppm 3.86 (s, 3H), 5.08 (s, 2H), 7.02 (m, 2H),7.30–7.42 (m, 7H), 7.62 (s, 1H), 8.81 (s, 1H); HPLC: RT 3.20 min, LC/MS:m/z 376 (M+1)⁺.

Example 754-Amino-3-(4-methoxyphenyl)-2-(2-phenylethen-1-yl)furo[2,3-d]pyrimidine

Example 75 was prepared according to procedures similar to those shownin Example 1.

1HNMR (400 MHz, CDCl3) ppm 3.91 (s, 3H), 5.07 (brs, 2H), 6.87 (d, J=16.2Hz, 1H), 7.01 (d, J=8.6 Hz, 2H), 7.29–7.46 (m, 6H), 7.43 (d, J=8.8 Hz,2H), 8.38 (s, 1H); HPLC: RT 3.52 min, LC/MS: m/z 344 (M+1)⁺.

Example 764-Amino-3-(4-methoxyphenyl)-2-(2-phenylethyl)furo[2,3-d]pyrimidine

Example 76 was prepared according to procedures similar to those shownin Example 1.

1HNMR (400 MHz, CDCl3) ppm 2.96–3.08 (m, 4H), 3.85 (s, 3H), 4.88 (brs,2H), 6.92 (d, J=8.8 Hz, 2H), 6.97 (d, J=8.6 Hz, 2H), 7.06–7.08 (m, 2H),7.19–7.24 (m, 3H), 8.35 (s, 1H); HPLC: RT 3.34 min, LC/MS: m/z 346(M+1)⁺.

Example 774-Amino-3-(4-methoxyphenyl)-2-(4-(morpholinocarbonyl)phenyl)-furo[2,3-d]pyrimidine

Example 77 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.74 min, LC/MS: m/z 431 (M+1)⁺.

Example 784-Amino-3-(4-methoxyphenyl)-2-(4-(N-methylcarbamoyl)phenyl)-furo[2,3-d]pyrimidine

Example 78 was prepared according to procedures similar to those shownin Example 1.

1HNMR (400 MHz, CDCl3) ppm 3.01 (d, 3H), 3.91 (s, 3H), 4.95 (brs, 2H),6.07 (brs, 1H), 7.07 (d, J=8.6 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 7.62 (d,J=8.8 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 8.40 (s, 1H); HPLC: RT 2.66 min,LC/MS: m/z 375 (M+1)⁺.

Example 79 4-Amino-3-(4-methoxyphenyl)-2-(4-(N-(2-(4-imidazolyl)ethyl)carbamoyl)phenyl)furo[2,3-d]pyrimidine

Example 79 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.55 min, LC/MS: m/z 455 (M+1)⁺.

Example 802,3-Bis(4-methoxyphenyl)-4,5-dihydro-4-imino-5-methylfuro[2,3-d]pyrimidine

Example 80 was prepared according to procedures similar to those shownin Scheme 1.

HPLC: RT 2.89 min, LC/MS: m/z.

Example 81 3,4-Bis(4-methoxyphenyl)-4-(methylamino)furo[2,3-d]pyrimidine

Example 81 was prepared according to procedures similar to those shownin Scheme 1.

HPLC: RT 3.43 min, LC/MS: m/z.

Example 824-Amino-3-(4-methoxyphenyl)-2-(4-(N-(2-dimethylaminoethyl)-carbamoyl)phenyl)furo[2,3-d]pyrimidine

Example 82 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.45 min, LC/MS: m/Z 432 (M+1)⁺.

Example 834-Amino-2-(1-hexen-1-yl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 83 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.71 min, LC/MS: m/z 324 (M+1)⁺.

Example 84 4-Amino-2-hexyl-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 84 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.73 min, LC/MS: m/z 326 (M+1)⁺.

Example 854-Amino-3-(2,4-dimethoxyphenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 85 was prepared according to procedures similar to those shownin Example 2.

HPLC: RT 3.15 min, LC/MS: m/z 378 (M+1)⁺.

Example 864-Amino-3-(4-methoxyphenyl)-2-(2-methoxypyridin-5-yl)furo[2,3-d]pyrimidine

Example 86 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, CDCl3) ppm 3.90 (s, 3H), 3.93 (s, 3H), 4.92 (brs, 2H),6.70 (dd, 1H, J=0.8 Hz, 8.8 Hz), 7.06 (m, 2H), 7.40 (m, 2H), 7.76 (dd,1H, J=2.5 Hz, 8.8 Hz), 8.35 (dd, 1H, J=0.8 Hz, 2.5 Hz), 8.38 (s, 1H);HPLC: RT 3.08 min, LC/MS: m/z 349 (M+1)⁺.

Example 874-Amino-2-(4-(dimethylamino)phenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 87 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 Hz, CDCl3) ppm 2.97 (s, 6H), 3.90 (s, 3H), 4.84 (s, 2H),6.60 (d, J=9.1 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H),7.44 (d, J=9.1 Hz, 2H), 8.33 (s, 1H); HPLC: RT 3.34 min, LC/MS: m/z 361(M+1)⁺.

Example 884-Amino-2-(2,4-dimethoxyphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 88 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.09 min, LC/MS: m/z 378 (M+1)⁺.

Example 894-Amino-2-(4-methoxyphenyl)-3-(2-methoxypyridin-5-yl)furo[2,3-d]pyrimidine

Example 89 was prepared according to procedures similar to those shownin Example 2.

1H NMR (400 MHz, CDCl3) ppm 3.81 (s, 3H), 4.03 (s, 3H), 4.87 (brs, 2H),6.85 (m, 2H), 6.91 (dd, 1H, J=0.8 Hz, 8.6 Hz), 7.48 (m, 2H), 7.68 (dd,1H, J=2.5 Hz, 8.6 Hz), 8.31 (dd, 1H, J=0.8 Hz, 2.5 Hz), 8.38 (s, 1H);HPLC: RT 3.02 min, LC/MS: m/z 349 (M+1)⁺.

Example 904-Amino-2-((3-chlorophenyl)oxymethyl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine

Example 90 was prepared according to procedures similar to those shownin Example 1.

1HNMR (400 MHz, CDCl3) ppm 6.84 (d, J=8.6 Hz, 2H), 6.89 (s, 1H), 6.96(d, J=8.6 2H), 7.05 (d, J=8.6 Hz, 2H), 7.19 (dd, J=8.1 Hz, 1H), 7.40 (d,J=8.6 Hz, 2H), 8.42 (s, 1H); HPLC: RT 3.37 min, LC/MS: m/z 382 (M+1)⁺,384 (M+3)⁺.

Example 914-Amino-2-((4-fluorophenyl)oxymethyl)-3-(4-methoxyphenyl)-furo2,3-d]pyrimidine

Example 91 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.19 min, LC/MS: m/z 366 (M+1)⁺.

Example 924-Amino-3-(4-methoxyphenyl)-2-((1-hydroxy-1-phenyl)methyl)-furo[2,3-d]pyrimidine

Example 92 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.84 min, LC/MS: m/z 348 (M+1)⁺.

Example 934-Amino-2-(3-carbamoylphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 93 was prepared according to procedures similar to those shownin Example 1.

1HNMR (400 MHz, CDCl3) ppm 3.91 (s, 3H), 4.97 (brs, 2H), 5.51 (brs, 1H),5.88 (brs, 1H), 7.09 (d, J=8.6 Hz, 2H), 7.36 (t, J=7.7 Hz, 1H), 7.43 (d,J=8.8 Hz, 2H), 7.63 (d, J=8.1 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 8.02 (s,1H), 8.40 (s, 1H); HPLC: RT 2.58 min, LC/MS: m/z 361 (M+1)⁺.

Example 94 4-Amino-2-(3-(N-dimethylcarbamoyl)phenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 94 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.68 min, LC/MS: m/z 389 (M+1)⁺.

Example 954-Amino-2-(1-methylindol-5-yl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 95 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.11 min, LC/MS: m/z 371 (M+1)⁺.

Example 964-Amino-2-((2-hydroxymethyl)phenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 96 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.72 min, LC/MS: m/z 348 (M+1)⁺.

Example 974-Amino-2-(3-aminophenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 97 was prepared according to procedures similar to those shownin Example 1.

1HNMR (400 MHz, CDCl3) ppm 3.65 (brs, 2H), 3.90 (s, 3H), 4.89 (brs, 2H),6.60 (dd, J=7.8, 1.7 Hz, 1H), 6.89 (d, J=7.8, 1H), 6.97 (m, 1H), 7.04(m, 1H), 7.05 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.6 Hz, 2H), 8.37 (s, 1H);HPLC: RT 2.78 min, LC/MS: m/z 333 (M+1)⁺.

Example 98 4-Amino-2-carboxy-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 98 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.09 min, LC/MS: m/z 286 (M+1)⁺.

Example 994-Amino-2-(2-carboxyphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 99 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.36 min, LC/MS: m/z 362 (M+1)⁺.

Example 1004-Amino-2-(3-methoxycarbonylphenyl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine

Example 100 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.07 min, LC/MS: m/z 376 (M+1)⁺.

Example 1014-Amino-2-(4-methoxyphenyl)-3-(1-methylindol-5-yl)furo[2,3-d]pyrimidine

Example 101 was prepared according to procedures similar to those shownin Example 2.

1H NMR (400 MHz, CDCl3) ppm 3.77 (s, 3H), 3.89 (s, 3H), 4.85 (brs, 2H),6.54 (m, 1H), 6.77 (m, 2H), 7.18 (m, 1H), 7.29 (m, 1H), 7.46–7.53 (m,3H), 7.74 (m, 1H), 8.36 (s, 1H); HPLC: RT 3.16 min, LC/MS: m/z 371(M+1)⁺.

Example 1024-Amino-2-(3-carboxyphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 102 was prepared according to procedures similar to those shownin Example 1.

1HNMR (400 MHz, DMSO-d6) ppm 4.09 (s, 3H), 7.39 (d, J=7.6 Hz, 2H),7.69–7.74 (m, 3H), 7.84 (d, J=7.8 Hz, 1H), 8.11 (d, J=7.8 Hz, 1H), 8.35(s, 1H), 8.53 (s, 1H); HPLC: RT 2.33 min, LC/MS: m/z 362 (M+1)⁺, 360(M−1)⁻.

Example 103 4-Amino-3-(4-methoxyphenyl)-2-(3-(N-(2-(4-imidazolyl)ethyl)carbamoyl)phenyl)furo[2,3-d]pyrimidine

Example 103 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.51 min, LC/MS: m/z 455 (M+1)⁺.

Example 1044-Amino-3-(4-methoxyphenyl)-2-(3-((4-methylpiperazin-1-yl)-carbonyl)phenyl)furo[2,3-d]pyrimidine

Example 104 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.58 min, LC/MS: m/z 444 (M+1)⁺.

Example 1054-Amino-3-(4-methoxyphenyl)-2-(3-(N-(2-dimethylaminoethyl)-carbamoyl)phenyl)furo[2,3-d]pyrimidine

Example 105 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, CDCl3) ppm 2.29 (s, 6H), 2.53 (t, J=4.0 Hz, 2H),3.49–3.54 (m, 2H), 3.90 (s, 3H), 4.98 (brs, 2H), 6.77 (brs, 1H), 7.07(d, J=8.8 Hz, 2H), 7.33 (dd, J=7.8 Hz, 1H), 7.42 (d, J=8.6 Hz, 2H), 7.57(m, 1H), 7.76 (m, 1H), 8.03 (brs, 1H), 8.40 (s, 1H) HPLC: RT 2.47 min,LC/MS: m/z 432 (M+1)⁺.

Example 1064-Amino-2-((2-cyanophenyl)oxymethyl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine

Example 106 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.93 min, LC/MS: m/z 374 (M+1)⁺.

Example 1074-Amino-2-((2-fluorophenyl)oxymethyl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine

Example 107 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.06 min, LC/MS: m/z 366 (M+1)⁺.

Example 1084-Amino-3-(4-methoxyphenyl)-2-(3-(N-(4-pyridyl)carbamoyl)-phenyl)furo[2,3-d]pyrimidine

Example 108 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.75 min, LC/MS: m/z 438 (M+1)⁺.

Example 1094-Amino-2-(2-carbamoylphenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 109 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.53 min, LC/MS: m/z 361 (M+1)⁺.

Example 1104-Amino-2-(4-carboxy-2-methoxyphenyl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine

Example 110 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.31 min, LC/MS: m/z 392 (M+1)⁺, 390 (M−1)⁻.

Example 1114-Amino-3-(4-methoxyphenyl)-2-(3-(N-(3-pyridyl)carbamoyl)-phenyl)furo[2,3-d]pyrimidine

Example 111 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.74 min, LC/MS: m/z 438 (M+1)⁺.

Example 1122-((3-Acetamidophenyl)oxymethyl)-4-amino-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine

Example 112 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.75 min, LC/MS: m/z 405 (M+1)⁺.

Example 1134-Amino-2-((3-cyanophenyl)oxymethyl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine

Example 113 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.10 min, LC/MS: m/z 373 (M+1)⁺.

Example 1144-Amino-2-(3-methoxycarbonyl-4-(methylamino)phenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 114 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, CDCl3) ppm 2.90 (d, 3H, J=5.0 Hz), 3.48(d, 1H, J=5.0Hz), 3.81 (s, 3H), 3.90 (s, 3H), 4.87 (brs, 2H), 6.54 (d, 1H, J=9.1 Hz),7.06 (m, 2H), 7.42 (m, 2H), 7.84 (m, 1H), 8.29 (d, 1H, J=2.3 Hz), 8.35(s, 1H); HPLC: RT 3.34 min, LC/MS: m/z 405 (M+1)⁺.

Example 1154-Amino-3-(4-methoxyphenyl)-2-(4-methylamino-3-carboxyphenyl)furo[2,3-d]pyrimidinehydrochloride

Example 115 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.48 min, LC/MS: m/z 391 (M+1)⁺, 389 (M−1)⁻.

Example 1164-Amino-2-(4-methoxyphenyl)-3-(4-(methylsulfonylamino)phenyl)furo[2,3-d]pyrimidine

Example 116 was prepared according to procedures similar to those shownin Example 2.

1H NMR (400 Hz, CDCl3) ppm 3.17 (s, 3H), 3.81 (s, 3H), 4.90 (s, 2H),6.62(s, 1H), 6.83 (d, J=9.1 Hz, 2H), 7.34 (d, J=8.6 Hz, 2H), 7.46 (d,J=9.1 Hz, 2H), 7.50 (d, J=8.6 Hz, 2H), 8.38 (s, 1H); HPLC: RT 2.85 min,LC/MS: m/z 411 (M+1)⁺, 409 (M−1)⁻.

Example 1174-Amino-3-(4-methoxyphenyl)-2-(N-(3-methylindazol-5-yl)carbamoyl)furo[2,3-d]pyrimidine

Example 117 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, DMSO-d6) ppm 2.60 (s, 3H), 4.00 (s, 3H), 7.24 (d, J=8.8Hz, 2H), 7.52 (d, J=8.6 Hz, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.76 (d, J=8.6Hz, 1H), 8.20 (s, 1H), 8.55 (s, 1H); HPLC: RT 2.69 min, LC/MS: m/z 415(M+1)⁺.

Example 118 4-Amino-2-((1,2-bis(ethoxycarbonyl)hydradino)methyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 118 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.77 min, LC/MS: m/z 430 (M+1)⁺.

Example 1194-Amino-3-(4-(diethylamino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 119 was prepared according to procedures similar to those shownin Example 2.

1H NMR (400 Hz, CDCl3) ppm 1.23 (t, J=7.3 Hz, 6H), 3.42 (q, J=7.3 Hz,4H), 3.80 (s, 3H), 5.02 (s, 2H), 6.76 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.8Hz, 2H), 7.26 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.8 Hz, 2H), 8.33 (s, 1H);HPLC: RT 3.70 min, LC/MS: m/z 389 (M+1)⁺.

Example 1204-Amino-3-(4-methoxyphenyl)-2-(N-phenylcarbamoyl)furo[2,3-d]pyrimidine

Example 120 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.98 min, LC/MS: m/z 361 (M+1)⁺.

Example 1214-Amino-2-(((5-amino-3-methyl)indazol-1-yl)carbonyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 121 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.79 min, LC/MS: m/z 415 (M+1)⁺.

Example 1224-Amino-3-(4-methoxyphenyl)-2-(1-pyrrolizinocarbonyl)furo[2,3-d]pyrimidine

Example 122 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.55 min, LC/MS: m/z 339 (M+1)⁺.

Example 1234-Amino-3-(4-methoxyphenyl)-2-((N,N-dicyclohexyl)carbamoyl)furo-[2,3-d]pyrimidine

Example 123 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.73 min, LC/MS: m/z 449 (M+1)⁺.

Example 1244-Amino-3-(4-methoxyphenyl)-2-(N-isopropylcarbamoyl)furo-[2,3-d]pyrimidine

Example 124 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, CDCl3) ppm 1.23 (d, J=6.6 Hz, 6H), 3.87 (s, 3H),4.16–4.23 (m, 1H), 5.24 (brs, 2H), 6.45 (br, 1H), 7.04 (d, J=8.8 Hz,2H), 7.50 (d, J=8.8 Hz, 2H), 8.44 (s, 1H); HPLC: RT 2.66 min, LC/MS: m/z327 (M+1)⁺.

Example 1254-Amino-3-(4-methoxyphenyl)-2-(N-(2-dimethylaminoethyl)carbamoyl)furo[2,3-d]pyrimidine

Example 125 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.24 min, LC/MS: m/z 356 (M+1)⁺.

Example 1264-Amino-2-(4-methoxyphenyl)-3-(4-(1-pyrrolidino)phenyl)furo[2,3-d]pyrimidine

Example 126 was prepared according to procedures similar to those shownin Example 2.

1H NMR (400 Hz, CDCl3) ppm 2.06–2.09 (m, 4H), 3.35–3.38 (m, 4H), 3.80(s, 3H), 4.96 (s, 2H), 6.66 (d, J=8.6 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H),7.29 (d, J=8.6 Hz, 2H), 7.57 (d, J=8.8 Hz, 2H), 8.34 (s, 1H); HPLC: RT3.69 min, LC/MS: m/z 387 (M+1)⁺.

Example 1274-Amino-2-(5-indolyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 127 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, DMSO-d6) ppm 3.85 (s, 3H), 6.42 (m, 1H), 7.11–7.17 (m,3H), 7.32–7.38 (m, 2H), 7.43 (m, 2H), 7.74 (s, 1H), 8.23 (s, 1H), 11.26(s, 1H); HPLC: RT 2.97 min, LC/MS: m/z 357 (M+1)⁺.

Example 1284-Amino-3-(4-methoxyphenyl)-2-((2-(phenylamino)ethyl)oxycarbonyl)furo[2,3-d]pyrimidine

Example 128 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.12 min, LC/MS: m/z 405 (M+1)⁺.

Example 1294-Amino-2-((3-hydroxypiperizin-1-yl)carbonyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 129 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.37 min, LC/MS: m/z 369 (M+1)⁺.

Example 1304-Amino-3-(4-methoxyphenyl)-2-((N-(2-cyanoethyl)-N-phenyl)carbamoyl)furo-[2,3-d]pyrimidine

Example 130 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.78 min, LC/MS: m/z 414 (M+1)⁺.

Example 1314-Amino-3-(4-biphenyl)-2-(3-carbamoylphenyl)furo[2,3-d]pyrimidine

Example 131 was prepared according to procedures similar to those shownin Example 7.

1H NMR (400 MHz, CDCl3) ppm 5.03 (brs, 2H), 5.50 (br, 1H), 5.93 (br,1H), 7.36–7.45 (m, 2H), 7.52 (m, 2H), 7.60 (m, 2H), 7.65–7.70 (m, 3H),7.79–7.83 (m, 3H), 8.03 (m, 1H), 8.43 (s, 1H); HPLC: RT 2.92 min, LC/MS:m/z 407 (M+1)⁺.

Example 1322-(3-Acetamidophenyl)-4-amino-3-(4-biphenyl)furo[2,3-d]pyrimidine

Example 132 was prepared according to procedures similar to those shownin Example 7.

1H NMR (400 MHz, CDCl3) ppm 2.16 (s, 3H), 4.98 (brs, 2H), 7.08 (s, 1H),7.23 (m, 2H), 7.42 (m, 1H), 7.51 (m, 2H), 7.58 (m, 3H), 7.70 (m, 3H),7.79 (m, 2H), 8.41 (s, 1H); HPLC: RT 3.10 min, LC/MS: m/z 421 (M+1)⁺.

Example 1334-Amino-3-(4-methoxyphenyl)-2-((N-(methoxycarbonylmethyl)-N-phenyl)carbamoyl)furo-[2,3-d]pyrimidine

Example 133 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.86 min, LC/MS: m/z 433 (M+1)⁺.

Example 1344-Amino-2-(3-carbamoyl-4-chlorophenyl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine

Example 134 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 Hz, CDCl3) ppm 3.90 (s, 3H), 5.07 (s, 2H), 5.83 (s, 1H),6.14 (s, 1H), 7.07 (d, J=8.6 Hz, 2H), 7.32 (d, J=8.6 Hz, 1H), 7.39 (d,J=8.6 Hz, 2H), 7.48 (dd, J=2.3, 8.6 Hz, 1H), 7.98 (d, J=2.3 Hz, 1H),8.39(s, 1H); HPLC: RT 2.69 min, LC/MS: m/z 395 (M+1)⁺.

Example 1354-Amino-2-(3-aminophenyl)-3-(4-biphenyl)furo[2,3-d]pyrimidine

Example 135 was prepared according to procedures similar to those shownin Example 7.

1H NMR (400 MHz, CDCl3) ppm 3.66 (brs, 2H), 4.95 (brs, 2H), 6.62 (m,1H), 6.91 (m, 1H), 7.01 (m, 1H), 7.05 (t, 1H, J=8.1 Hz), 7.42 (m, 1H),7.51 (m, 2H), 7.58 (m, 2H), 7.70 (m, 2H), 7.77 (m, 2H), 8.40 (s, 1H);HPLC: RT 3.22 min, LC/MS: m/z 379 (M+1)⁺.

Example 1364-Amino-2-(3-(aminomethyl)phenyl)-3-(4-biphenyl)furo[2,3-d]pyrimidine

Example 136 was prepared according to procedures similar to those shownin Example 7.

HPLC: RT 2.80 min, LC/MS: m/z 393 (M+1)⁺.

Example 1374-Amino-3-(4-biphenyl)-2-(4-(dimethylamino)phenyl)furo[2,3-d]pyrimidine

Example 137 was prepared according to procedures similar to those shownin Example 7.

1H NMR (400 MHz, CDCl3) ppm 2.97 (s, 6H), 4.90 (brs, 2H), 6.61 (m, 2H),7.41 (m, 1H), 7.47–7.52 (m, 4H), 7.58 (m, 2H), 7.69 (m, 2H), 7.76 (m,2H), 8.35 (s, 1H), HPLC: RT 3.86 min, LC/MS: m/z 407 (M+1)⁺.

Example 1384-Amino-2-((N-(2-(tert-butoxycarbonylamino)ethyl)-N-phenyl)carbamoyl)-3-(4-methoxyphenyl)furo-[2,3-d]pyrimidine

Example 138 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.04 min, LC/MS: m/z 504 (M+1)⁺.

Example 1394-Amino-3-(4-methoxyphenyl)-2-((N-carboxymethyl-N-phenyl)carbamoyl)furo-[2,3-d]pyrimidine

Example 139 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.26 min, LC/MS: m/z 419 (M+1)⁺, 417 (M−1)⁻.

Example 1404-Amino-2-carbamoyl-3-(4-methoxyphenyl)furo-[2,3-d]pyrimidine

Example 140 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, CDCl3) ppm 3.88 (s, 3H), 5.22 (brs, 2H), 5.51 (brs,1H), 6.48 (brs, 1H), 7.05 (d, J=8.6 Hz, 2H), 7.50 (d, J=8.6 Hz, 2H),8.46 (s, 1H); HPLC: RT 2.27 min, LC/MS: m/z 285 (M+1)⁺.

Example 1414-Amino-3-(4-methoxyphenyl)-2-(3-((2-morpholinoethyl)-sulfonylamino)phenyl)furo[2,3-d]pyrimidine

Example 141 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, CDCl3) ppm 2.46 (m, 4H), 2.86 (t, 2H, J=6.3 Hz), 3.19(t, 2H, J=6.3 Hz), 3.66 (m, 4H), 3.90 (s, 3H), 4.93 (brs, 2H), 7.08 (m,2H), 7.20–7.29 (m, 2H), 7.33 (m, 2H), 7.41 (m, 2H), 8.39 (s, 1H); HPLC:RT 2.76 min, LC/MS: m/z 510 (M+1)⁺, 508 (M−1)⁻.

Example 142 4-Amino-3-(4-methoxyphenyl)-2-((2-methyl)benzothiazol-5-yl)furo[2,3-d]pyrimidine

Example 142 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, CDCl3) ppm 2.82 (s, 3H), 3.90 (s, 3H), 4.92 (brs, 2H),7.06 (m, 2H), 7.44 (m, 2H), 7.65 (dd, 1H, J=1.5 Hz, 8.6 Hz), 7.76 (d,1H, J=8.6 Hz), 8.10 (d, 1H, J=1.5 Hz), 8.40 (s, 1H); HPLC: RT 3.19 min,LC/MS: m/z 389 (M+1)⁺.

Example 1434-Amino-2-(6-indolyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 143 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, CDCl3) ppm 3.91 (s, 3H), 4.88 (brs, 2H), 6.52 (m, 1H),7.06 (m, 2H), 7.44 (m, 2H), 7.51 (d, 1H, J=8.4 Hz), 7.71 (s, 1H), 8.19(br, 1H), 8.37(s, 1H); HPLC: RT 3.10 min, LC/MS: m/z 357 (M+1)⁺.

Example 1444-Amino-2-(3-carbamoyl-4-fluorophenyl)-3-(4-methoxyphenyl)furo-[2,3-d]pyrimidine

Example 144 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.66 min, LC/MS: m/z 379 (M+1)⁺.

Example 1454-Amino-3-(4-biphenyl)-2-(3-carbamoyl-4-fluorophenyl)furo[2,3-d]pyrimidine

Example 145 was prepared according to procedures similar to those shownin Example 7.

1H NMR (400 MHz, CDCl3) ppm 5.01 (brs, 2H), 5.72 (br, 1H), 6.56 (br,1H), 7.08 (dd, 1H, J=8.6 Hz, 11.4 Hz), 7.41 (m, 1H), 7.50 (m, 2H), 7.57(m, 2H), 7.46–7.70 (m, 3H), 7.80 (m, 2H), 8.43 (m, 2H); HPLC: RT 2.98min, LC/MS: m/z 425 (M+1)⁺.

Example 1464-Amino-2-((4-hydroxypiperizin-1-yl)carbonyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 146 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.29 min, LC/MS: m/z 369 (M+1)⁺.

Example 1474-Amino-2-(4-amino-3-(N-methylcarbamoyl)phenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 147 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.66 min, LC/MS: m/z 390 (M+1)⁺.

Example 1484-Amino-2-((N-(carbamoylmethyl)-N-phenyl)carbamoyl)-3-(4-methoxyphenyl)furo-[2,3-d]pyrimidine

Example 148 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.39 min, LC/MS: m/z 418 (M+1)⁺.

Example 1494-Amino-2-((N-(2-(aminocarbonylamino)ethyl)-N-phenyl)carbamoyl)-3-(4-methoxyphenyl)furo-[2,3-d]pyrimidine

Example 149 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.42 min, LC/MS: m/z 447 (M+1)⁺.

Example 1504-Amino-2-(2-aminoxadiazol-5-yl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 150 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, DMSO-d6) ppm 3.84 (s, 3H), 7.10 (d, J=8.8 Hz, 2H), 7.39(s, 2H), 7.52 (d, J=8.6 Hz, 2H), 8.32 (s, 1H); HPLC: RT 2.33 min, LC/MS:m/z 325 (M+1)⁺.

Example 1514-Amino-2-(4-(ethoxycarbonyl)thiazol-2-yl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine

Example 151 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.93 min, LC/MS: m/z 397 (M+1)⁺.

Example 1524-Amino-2-((4-(4-fluorophenyl)-5-methyl)thiazol-2-yl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine

Example 152 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.55 min, LC/MS: m/z 433 (M+1)⁺.

Example 1534-Amino-2-(5-indolyl)-3-(4-(3-pyridyl)phenyl)furo[2,3-d]pyrimidine

Example 153 was prepared according to procedures similar to those shownin Example 5.

1H NMR (400 MHz, CDCl3) ppm 4.95 (brs, 2H), 6.52 (m, 1H), 7.22–7.49 (m,5H), 7.67 (m, 2H), 7.77 (m, 2H), 7.94 (m, 1H), 7.98 (m, 1H), 8.26 (br,1H), 8.39 (s, 1H), 8.66 (m, 1H), 8.97 (m, 1H); HPLC: RT 2.85 min, LC/MS:m/z 404 (M+1)⁺.

Example 1544-Amino-2-(2-imidazolin-2-yl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 154 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.12 min, LC/MS: m/z 310 (M+1)⁺.

Example 1554-Amino-2-(2-(phenylamino)oxadiazol-5-yl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 155 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.86 min, LC/MS: m/z 401 (M+1)⁺.

Example 1564-Amino-2-(8H-indeno[1,2-d]thiazol-2-yl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 156 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.34 min, LC/MS: m/z 413 (M+1)⁺.

Example 1574-Amino-3-(4-methoxyphenyl)-2-(4-methylthiazol-2-yl)furo[2,3-d]pyrimidine

Example 157 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, CDCl3) ppm 2.46 (s, 3H), 3.91 (s, 3H), 5.05 (brs, 2H),6.84 (s, 1H), 7.08 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.6 Hz, 2H), 8.43 (s,1H); HPLC: RT 2.81 min, LC/MS: m/z 339 (M+1)⁺.

Example 1584-Amino-2-((3-(2-(dimethylamino)ethyl)aminocarbonylamino)phenyl)-3-(4-methoxyphenyl)furo-[2,3-d]pyrimidine

Example 158 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, CDCl3) ppm 2.29 (s, 6H), 2.50 (m, 2H), 3.30 (m, 2H),3.90 (s, 3H), 4.94 (brs, 2H), 5.21 (br, 1H), 7.05 (m, 2H), 7.10 (m, 1H),7.18 (t, 1H, J=8.0 Hz), 7.35 (m, 1H), 7.40 (m, 2H), 7.56 (m, 1H), 8.37(s, 1H); HPLC: RT 2.49 min, LC/MS: m/z 447 (M+1)⁺, 445 (M−1)⁻.

Example 1594-Amino-3-(4-biphenyl)-2-((3-(2-(dimethylamino)ethyl)-aminocarbonylamino)phenyl)furo-[2,3-d]pyrimidine

Example 159 was prepared according to procedures similar to those shownin Example 7.

HPLC: RT 2.77 min, LC/MS: m/z 493 (M+1)⁺, 491 (M−1)⁻.

Example 1604-Amino-3-(4-biphenyl)-2-(3-(methylsulfonylamino)phenyl)furo[2,3-d]pyrimidine

Example 160 was prepared according to procedures similar to those shownin Example 7.

1H NMR (400 MHz, CDCl3) ppm 2.89 (s, 3H), 5.01 (brs, 2H), 6.30 (m, 1H),7.15 (m, 1H), 7.31 (t, 1H, J=7.9 Hz), 7.37 (m, 1H), 7.43 (m, 2H), 7.51(m, 2H), 7.58 (m, 2H), 7.68 (m, 2H), 7.80 (m, 2H), 8.42 (s, 1H); HPLC:RT 3.17 min, LC/MS: m/z 452 (M+1)⁺.

Example 1614-Amino-3-(4-methoxyphenyl)-2-(4-(N-methylcarbamoyl)thiazol-2-yl)furo[2,3-d]pyrimidine

Example 161 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.61 min, LC/MS: m/z 382 (M+1)⁺.

Example 1624-Amino-3-(4-(3-fluorophenyl)phenyl)-2-(3-(methylsulfonylamino)phenyl)furo[2,3-d]pyrimidine

Example 162 was prepared according to procedures similar to those shownin Example 5.

1H NMR (400 Hz, DMSO-d6) ppm 2.88 (s, 3H), 7.13–7.15 (m, 2H), 7.23–7.33(m, 2H), 7.44 (t, J=1.8 Hz, 1H), 7.53–7.67 (m, 5H), 7.92 (d, J=8.3 Hz,2H), 8.30 (s, 1H), 9.90 (s, 1H); HPLC: RT 3.15 min, LC/MS: m/z 475(M+1)⁺, 473 (M−1)⁻.

Example 1634-Amino-3-(4-methoxyphenyl)-2-(4-(N-phenylcarbamoyl)thiazol-2-yl)furo[2,3-d]pyrimidine

Example 163 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.24 min, LC/MS: m/z 444 (M+1)⁺.

Example 1644-Amino-2-(1-benzyl-4,5-dihydro-1H-imidazol-2-yl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 164 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.67 min, LC/MS: m/z 400 (M+1)⁺.

Example 1654-Amino-3-(4-methoxyphenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine

Example 165 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, DMSO-d6) ppm 3.85 (s, 3H), 7.14 (m, 2H), 7.41–7.52 (m,4H), 7.74 (m, 1H), 8.12 (m, 1H), 8.30 (s, 1H); HPLC: RT 2.73 min, LC/MS:m/z 397 (M+1)⁺.

Example 1664-Amino-3-(4-biphenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine

Example 166 was prepared according to procedures similar to those shownin Example 7.

1H NMR (400 MHz, CDCl3) ppm 4.71 (s, 2H), 5.04 (brs, 2H), 7.43 (m, 2H),7.51(m, 2H), 7.58 (m, 2H), 7.69 (m, 3H), 7.82 (m, 3H), 8.23 (m, 1H),8.44 (s, 1H); HPLC: RT 3.05 min, LC/MS: m/z 443 (M+1)⁺.

Example 1674-Amino-3-(4-methoxyphenyl)-2-(2-oxadiazolyl)furo[2,3-d]pyrimidine

Example 167 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, CDCl3) ppm 3.90 (s, 3H), 5.26 (brs, 2H), 7.09 (d, J=8.8Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 8.43 (s, 1H), 8.49 (s, 1H); HPLC: RT2.51 min, LC/MS: m/z 310 (M+1)⁺.

Example 1684-Amino-3-(4-methoxyphenyl)-2-(5,6,7,7a-tetrahydro-1H-pyrrolo[1,2–C]imidazol-3-yl)furo[2,3-d]pyrimidine

Example 168 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.44 min, LC/MS: m/z 350 (M+1)⁺.

Example 1694-Amino-2-(4-carboxythiazol-2-yl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 169 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.22 min, LC/MS: m/z 369 (M+1)⁺, 367 (M−1)⁻.

Example 1704-Amino-2-(3-(methylsulfonylamino)phenyl)furo[2,3-d]pyrimidine

Example 170 was prepared according to procedures similar to those shownin Example 2(B).

HPLC: RT 2.48 min, LC/MS: m/z 305 (M+1)⁺, 303 (M−1)⁻.

Example 1714-Amino-3-(4-methoxyphenyl)-2-(N-(2-phenylethyl)carbamoyl)-furo[2,3-d]pyrimidine

Example 171 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.95 min, LC/MS: m/z 389 (M+1)⁺.

Example 1724-Amino-2-(N-(3-fluorophenyl)carbamoyl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine

Example 172 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.04 min, LC/MS: m/z 379 (M+1)⁺.

Example 1734-Amino-2-(N-(4-chlorophenyl)carbamoyl)-3-(4-methoxyphenyl)-furo[2,3-d]pyrimidine

Example 173 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, CDCl3) ppm 3.89 (s, 3H), 5.19 (brs, 2H), 7.07 (d, J=8.6Hz, 2H), 7.30 (d, J=8.8 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.59 (d, J=8.8Hz, 2H), 8.37 (brs, 1H), 8.49 (s, 1H); HPLC: RT 3.19 min, LC/MS: m/z 395(M+1)⁺, 397 (M+3)⁺.

Example 1744-Amino-3-(4-methoxyphenyl)-2-(N-(4-methoxyphenyl)carbamoyl)-furo[2,3-d]pyrimidine

Example 174 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.91 min, LC/MS: m/z 391 (M+1)⁺.

Example 1754-Amino-2-(N-(2-benzoimidazolyl)carbamoyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 175 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.77 min, LC/MS: m/z 401 (M+1)⁺.

Example 1764-Amino-3-(4-(2,3-difluorophenyl)phenyl)-2-(4-fluoro-3-(methylsulfonylamino)phenyl)furo[2,3-d]pyrimidine

Example 176 was prepared according to procedures similar to those shownin Example 5.

1H NMR (400 Hz, DMSO-d6) ppm 2.87 (s, 3H), 7.31–7.39 (m, 3H), 7.46–7.52(m, 3H), 7.65 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.3 Hz, 2H), 8.30 (s, 1H);HPLC: RT 3.14 min, LC/MS: m/z 511 (M+1)⁺, 509 (M−1)⁻.

Example 1774-Amino-2-(N-(2-hydroxyphenyl)carbamoyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 177 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.68 min, LC/MS: m/z 377 (M+1)⁺, 375 (M−1)⁻.

Example 1784-Amino-2-(4-fluoro-3-(methylsulfonylamino)phenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 178 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.77 min, LC/MS: m/z 429 (M+1)⁺.

Example 1794-Amino-3-(4-biphenyl)-2-(4-fluoro-3-(methylsulfonylamino)phenyl)furo[2,3-d]pyrimidine

Example 179 was prepared according to procedures similar to those shownin Example 7.

HPLC: RT 3.10 min, LC/MS: m/z 475 (M+1)⁺.

Example 1804-Amino-2-((6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)carbonyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 180 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.69 min, LC/MS: m/z 461 (M+1)⁺.

Example 1814-Amino-2-(N-(2-carbamoylphenyl)carbamoyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 181 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.81 min, LC/MS: m/z 404 (M+1)⁺.

Example 1824-Amino-2-(4-fluoro-3-(methylsulfonylamino)phenyl)-3-(4-(3-thienyl)phenyl)furo[2,3-d]pyrimidine

Example 182 was prepared according to procedures similar to those shownin Example 5.

1H NMR (400 MHz, CDCl3) ppm 2.87 (s, 3H), 5.01 (brs, 2H), 6.59 (br, 1H),7.09 (m, 1H), 7.42–7.73 (m, 7H), 7.78 (m, 2H), 8.40 (s, 1H); HPLC: RT3.06 min, LC/MS: m/z 481 (M+1)⁺.

Example 1834-Amino-2-(3-(aminocarbonylamino)phenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 183 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.61 min, LC/MS: m/z 376 (M+1)⁺, 374 (M−1)⁻.

Example 1844-Amino-2-(3-(aminocarbonylamino)phenyl)-3-(4-biphenyl)furo[2,3-d]pyrimidine

Example 184 was prepared according to procedures similar to those shownin Example 7.

1H NMR (400 MHz, DMSO-d6) ppm 5.88 (brs, 2H), 6.84 (m, 1H), 7.13 (t, 1H,J=8.0 Hz), 7.33 (m, 1H), 7.41 (m, 1H), 7.52 (m, 2H), 7.59 (m, 2H), 7.81(m, 3H), 7.89 (m, 2H), 8.28 (s, 1H), 8.65 (s, 1H); HPLC: RT 2.90 min,LC/MS: m/z 422 (M+1)⁺, 420 (M−1)⁻.

Example 1854-Amino-2-(N-(3-cyanophenyl)carbamoyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 185 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.95 min, LC/MS: m/z 386 (M+1)⁺.

Example 1864-Amino-3-(4-methoxyphenyl)-2-(N-(3-pyridyl)carbamoyl)furo[2,3-d]pyrimidine

Example 186 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.55 min, LC/MS: m/z 362 (M+1)⁺.

Example 1874-Amino-2-(N-(α-cyanobenzyl)carbamoyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 187 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.92 min, LC/MS: m/z 400 (M+1)⁺.

Example 1884-Amino-2-(N-(3,5-dimethoxyphenyl)carbamoyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 188 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 3.02 min, LC/MS: m/z 421 (M+1)⁺.

Example 1894-Amino-3-(4-biphenyl)-2-(4-methoxy-3-(methylsulfonylamino)phenyl)furo[2,3-d]pyrimidine

Example 189 was prepared according to procedures similar to those shownin Example 7.

HPLC: RT 3.17 min, LC/MS: m/z 487 (M+1)⁺, 485 (M−1)⁻.

Example 1904-Amino-3-(4-biphenyl)-2-(3-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 190 was prepared according to procedures similar to those shownin Example 7.

1H NMR (400 MHz, CDCl3) ppm 5.00 (brs, 2H), 7.01 (br, 1H), 7.11–7.16 (m,2H), 7.22–7.27 (m, 1H), 7.38–7.42 (m, 1H), 7.46–7.50 (m, 3H), 7.57 (m,3H), 7.64 (m, 2H), 7.75 (d, J=8.1 Hz, 2H), 8.40 (s, 1H), 8.57–8.59 (m,1H); HPLC: RT 3.96 min, LC/MS: m/z 584 (M+1)⁺.

Example 1914-Amino-3-(4-biphenyl)-2-(4-(methylsulfonylamino)phenyl)furo[2,3-d]pyrimidine

Example 191 was prepared according to procedures similar to those shownin Example 7.

HPLC: RT 3.14 min, LC/MS: m/z 457 (M+1)⁺.

Example 1924-Amino-3-(4-biphenyl)-2-(4-(aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 192 was prepared according to procedures similar to those shownin Example 7.

HPLC: RT 2.86 min, LC/MS: m/z 422 (M+1)⁺, 420 (M−1)⁻.

Example 1934-Amino-3-(4-biphenyl)-2-(3-((4-pyridylcarbonyl)amino)phenyl)-furo[2,3-d]pyrimidine

Example 193 was prepared according to procedures similar to those shownin Example 7.

HPLC: RT 3.14 min, LC/MS: m/z 484 (M+1)⁺.

Example 1944-Amino-3-(4-methoxyphenyl)-2-(4-(methylsulfonylamino)-phenyl)furo[2,3-d]pyrimidine

Example 194 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 MHz, CDCl3) ppm 3.03 (s, 3H), 3.91 (s, 3H), 4.91 (brs, 2H),6.35 (s, 1H), 7.07 (m, 2H), 7.11 (m, 2H), 7.40 (m, 2H), 7.56 (m, 2H),8.38 (s, 1H); HPLC: RT 2.76 min, LC/MS: m/z 411(M+1)⁺.

Example 1954-Amino-2-(4-(aminocarbonylamino)phenyl)-3-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 195 was prepared according to procedures similar to those shownin Example 1.

HPLC: RT 2.54 min, LC/MS: m/z 376 (M+1)⁺, 374 (M−1)⁻.

Example 1964-Amino-2-(5-benzotriazolyl)-3-(4-biphenyl)furo[2,3-d]pyrimidine

Example 196 was prepared according to procedures similar to those shownin Example 7.

1H NMR (400 MHz, DMSO-d6) ppm 7.36–7.44 (m, 2H), 7.51–7.59 (m, 3H), 7.62(d, J=8.3 Hz, 2H), 7.70 (s, 1H), 7.82 (d, J=8.6 Hz, 2H), 7.91 (d, J=8.3Hz, 2H), 8.25 (s, 1H), 8.31 (s, 1H);

HPLC: RT 2.92 min, LC/MS: m/z 405 (M+1)⁺.

Example 1974-Amino-3-(4-biphenyl)-2-(3-(p-toluenesulfonylamino)phenyl)-furo[2,3-d]pyrimidine

Example 197 was prepared according to procedures similar to those shownin Example 7.

HPLC: RT 3.50 min, LC/MS: m/z 533 (M+1)⁺.

Example 1984-Amino-2-(5-benzimidazolyl)-3-(4-biphenyl)furo[2,3-d]pyrimidine

Example 198 was prepared according to procedures similar to those shownin Example 7.

HPLC: RT 2.84 min, LC/MS: m/z 404 (M+1)⁺.

Example 1994-Amino-3-(4-biphenyl)-2-(4-sulfamoylphenyl)furo[2,3-d]pyrimidine

Example 199 was prepared according to procedures similar to those shownin Example 7.

1H NMR (400 Hz, DMSO-d6) ppm 7.42 (t, J=7.3 Hz, 1H), 7.52 (t, J=7.6 Hz,2H), 7.61–7.64 (m, 4H), 7.78–7.83 (m, 4H), 7.91 (d, J=8.3 Hz, 2H), 8.32(s, 1H); HPLC: RT 3.00 min, LC/MS: m/z 443 (M+1)⁺, 441 (M−1)⁻.

Example 2004-Amino-3-(4-biphenyl)-2-(3-(N-methylsulfonyl)phenyl)furo[2,3-d]pyrimidine

Example 200 was prepared according to procedures similar to those shownin Example 7.

1H NMR (400 Hz, CDCl3) ppm 2.58 (d, J=5.6 Hz, 3H), 4.22(q, J=5.6 Hz,1H), 5.04 (s, 2H), 7.41–7.59 (m, 6H), 7.67–7.81 (m, 6H), 8.10 (t, J=1.8Hz, 1H), 8.44 (s, 1H); HPLC: RT 3.16 min, LC/MS: m/z 457 (M+1)⁺, 455(M−1)⁻.

Example 2014-Amino-2-(4-fluoro-3-(methylsulfonylamino)phenyl)-3-(4-(2-pyridyl)phenyl)furo[2,3-d]pyrimidine

Example 201 was prepared according to procedures similar to those shownin Example 5.

1H NMR (400 MHz, CDCl3) ppm 2.89 (s, 3H), 5.00 (brs, 2H), 6.52 (s, 1H),7.10 (m, 1H), 7.32 (m, 1H), 7.43 (m, 1H), 7.62 (m, 2H), 7.67 (m, 1H),7.83 (m, 2H), 8.18 (m, 2H), 8.40 (s, 1H), 8.74 (m, 1H); HPLC: RT 2.78min, LC/MS: m/z 476 (M+1)⁺.

Example 2024-Amino-3-(4-biphenyl)-2-(4-((dimethylamino)sulfonylamino)-phenyl)furo[2,3-d]pyrimidine

Example 202 was prepared according to procedures similar to those shownin Example 7.

HPLC: RT 3.26 min, LC/MS: m/z 486 (M+1)⁺.

Example 2034-Amino-3-(4-biphenyl)-2-(4-((1-iminoethyl)amino)phenyl)furo[2,3-d]pyrimidine

Example 203 was prepared according to procedures similar to those shownin Example 7.

HPLC: RT 2.68 min, LC/MS: m/z 420 (M+1)⁺;

Example 2044-Amino-3-(4-(4-tert-butylphenyl)phenyl)-2-(3-sulfamoylphenyl)-furo[2,3-d]pyrimidine

Example 204 was prepared according to procedures similar to those shownin Example 5.

HPLC: RT 3.50 min, LC/MS: m/z 499 (M+1)⁺.

Example 2054-Amino-3-(4-biphenyl)-2-(3-((dimethylamino)sulfonylamino)-phenyl)furo[2,3-d]pyrimidine

Example 205 was prepared according to procedures similar to those shownin Example 7.

1H NMR (400 Hz, CDCl3) ppm 2.76 (s, 6H), 4.99 (s, 2H), 6.30 (s, 1H),7.12–7.16 (m, 1H), 7.24–7.28 (m, 1H), 7.34–7.37 (m, 2H), 7.42 (t, J=7.3Hz, 1H), 7.51 (t, J=7.8 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.68–7.70 (m,2H), 7.79 (d, J=8.3 Hz, 2H), 8.41 (s, 1H); HPLC: RT 3.27 min, LC/MS: m/z486 (M+1)⁺, 484 (M−1)⁻.

Example 2064-Amino-3-(4-(2-pyridyl)phenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine

Example 206 was prepared according to procedures similar to those shownin Example 5.

HPLC: RT 2.71 min, LC/MS: m/z 444 (M+1)⁺.

Example 2074-Amino-3-(4-(3-pyridyl)phenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine

Example 207 was prepared according to procedures similar to those shownin Example 5.

1H NMR (400 MHz, DMSO-d6) ppm 7.46–7.56 (m, 5H), 7.66 (d, J=8.3 Hz, 2H),7.76 (ddd, J=1.6 Hz, 7.5 Hz, 1H), 7.80 (d, J=8.3 Hz, 2H), 8.11 (m, 1H),8.21 (ddd, J=2.0 Hz, 8.3 Hz, 1H), 8.32 (s, 1H), 8.63 (dd, J=4.8 Hz, 1.5Hz), 9.03 (m, 1H); HPLC: RT 2.61 min, LC/MS: m/z 444 (M+1)⁺.

Example 2084-Amino-3-(4-biphenyl)-2-(4-cyanophenyl)furo[2,3-d]pyrimidine

Example 208 was prepared according to procedures similar to those shownin Example 7.

1H NMR (400 Hz, CDCl3) ppm 5.04 (s, 2H), 7.42–7.59 (m, 7H), 7.68–7.71(m, 4H), 7.82 (d, J=8.3 Hz, 2H), 8.44 (s, 1H); HPLC: RT 3.52 min, LC/MS:m/z 389 (M+1)⁺.

Example 2094-Amino-3-(4-biphenyl)-2-(4-(tetrazol-5-yl)phenyl)furo[2,3-d]pyrimidinehydrochloride

Example 209 was prepared according to procedures similar to those shownin Example 7.

1H NMR (400 Hz, DMSO-d6) ppm 7.43 (t, J=7.3 Hz, 1H), 7.53 (t, J=7.3 Hz,2H), 7.64 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.6 Hz, 2H), 7.83 (d, J=8.6 Hz,2H), 7.93 (d, J=8.4 Hz, 2H), 8.02 (d, J=8.6 Hz, 2H), 8.33 (s, 1H); HPLC:RT 2.60 min, LC/MS: m/z 432 (M+1)⁺, 430 (M−1)⁻.

Example 2104-Amino-3-(4-biphenyl)-2-(3-(tetrazol-5-yl)phenyl)furo[2,3-d]pyrimidine

Example 210 was prepared according to procedures similar to those shownin Example 7.

1H NMR (400 Hz, DMSO-d6) ppm 7.33 (d, J=8.3 Hz, 1H), 7.39–7.44 (m, 2H),7.52 (t, J=7.3 Hz, 2H), 7.64 (d, J=8.3 Hz, 2H), 7.81 (d, J=7.3 Hz, 2H),7.90 (d, J=8.3 Hz, 2H), 7.96 (d, J=7.8 Hz, 1H), 8.33 (s, 1H), 8.38 (s,1H); HPLC: RT 2.67 min, LC/MS: m/z 432 (M+1)⁺, 430 (M−1)⁻.

Example 2114-Amino-3-(4-(1-naphthyl)phenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine

Example 211 was prepared according to procedures similar to those shownin Example 5.

HPLC: RT 3.26 min, LC/MS: m/z 493 (M+1)⁺.

Example 2124-Amino-3-(4-(4-(ethylsulfonyl)phenyl)phenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine

Example 212 was prepared according to procedures similar to those shownin Example 5.

HPLC: RT 2.79 min, LC/MS: m/z 432 (M+1)⁺.

Example 2134-Amino-2,3-bis(4-methoxyphenyl)-6-(ethoxycarbonyl)furo[2,3-d]pyrimidine

Example 213 was prepared according to procedures similar to those shownin Scheme 1.

1H NMR (400 MHz, CDCl3) ppm 1.32 (t, J=7.2 Hz, 3H), 3.81 (s, 3H), 3.90(s, 3H), 4.54 (q, J=7.2 Hz, 2H), 5.19 (brs, 2H), 6.83 (d, J=9.1 Hz, 2H),7.06 (d, J=8.6 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H);HPLC: RT 3.35 min, LC/MS: m/z 420 (M+1)⁺.

Example 2144-Amino-3-(4-(4,6-bis(trifluoromethyl)phenyl)phenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine

Example 214 was prepared according to procedures similar to those shownin Example 5.

HPLC: RT 3.43 min, LC/MS: m/z 579 (M+1)⁺.

Example 2154-Amino-3-(4-(2-fluorobiphen-4-yl)phenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine

Example 215 was prepared according to procedures similar to those shownin Example 6.

1H NMR (400 MHz, CDCl3) ppm 4.80 (brs, 2H), 5.06 (brs, 2H), 7.41–7.71(m, 12H), 7.84 (m, 3H), 8.23 (m, 1H), 8.44 (s, 1H); HPLC: RT 3.41 min,LC/MS: m/z 537 (M+1)⁺.

Example 2164-Amino-2,3-bis(4-methoxyphenyl)-6-carbamoylfuro[2,3-d]pyrimidine

Example 216 was prepared according to procedures similar to those shownin Scheme 1.

1H NMR (400 MHz, DMSO-d6) ppm 3.76 (s, 3H), 3.85 (s, 3H), 6.69 (d, J=8.8Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 7.40–7.44 (m, 4H), 7.62 (brs, 1H), 7.93(brs, 1H); HPLC RT 2.98 min, LC/MS: m/z 391 (M+1)⁺.

Example 2174-Amino-3-(4-((4-chlorophenyl)aminocarbonylamino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 217 was prepared according to procedures similar to those shownin Example 4.

1H NMR (400 MHz, DMSO-d6) ppm 3.75 (s, 3H), 6.94 (d, J=9.1 Hz, 2H), 7.35(d, J=8.8 Hz, 2H), 7.40–7.42 (m, 4H), 7.52 (d, J=8.8 Hz, 2H), 7.65 (d,J=8.6 Hz, 2H), 8.24 (s, 1H), 8.97 (brs, 1H), 9.02 (brs, 1H); HPLC: RT3.41 min, LC/MS: m/z 486 (M+1)⁺, 488 (M+3)⁺.

Example 2184-Amino-3-(4-methoxyphenyl)-2-(4-(tetrazol-5-yl)phenyl)furo[2,3-d]pyrimidinehydrochloride

Example 218 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 Hz, DMSO-d6) ppm 3.87 (s, 3H), 7.16 (d, J=8.8 Hz, 2H), 7.47(d, J=8.6 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 8.00 (d, J=8.6 Hz, 2H), 8.30(s, 1H); HPLC: RT min, LC/MS: m/z 386 (M+1)⁺, 384 (M−1)⁻.

Example 2194-Amino-3-(4-methoxyphenyl)-2-(3-(tetrazol-5-yl)phenyl)furo[2,3-d]pyrimidinehydrochloride

Example 219 was prepared according to procedures similar to those shownin Example 1.

1H NMR (400 Hz, DMSO-d6) ppm 3.86 (s, 3H), 7.15 (d, J=8.8 Hz, 2H),7.44–7.56 (m, 4H), 7.97 (d, J=7.8 Hz, 1H), 8.31 (s, 1H), 8.37 (s, 1H);HPLC: RT 2.39 min, LC/MS: m/z 386 (M+1)⁺, 384 (M−1)⁻.

Example 2204-Amino-3-(4-((3-fluorobenzoyl)amino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 220 was prepared according to procedures similar to those shownin Example 3.

1H NMR (400 MHz, DMSO-d6) ppm 3.76 (s, 3H), 6.95 (d, J=8.8 Hz, 2H), 7.41(d, J=8.8 Hz, 2H), 7.46–7.51 (m, 3H), 7.60–7.65 (m, 1H), 7.78–7.85 (m,2H), 8.00 (d, J=8.6 Hz, 2H), 8.25 (s, 1H); HPLC: RT 3.28 min, LC/MS: m/z455 (M+1)⁺, 453 (M−1)⁻.

Example 2214-Amino-3-(4-((2-fluorobenzoyl)amino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 221 was prepared according to procedures similar to those shownin Example 3.

HPLC: RT 3.27 min, LC/MS: m/z 455 (M+1)⁺, 453 (M−1)⁻.

Example 2224-Amino-2,3-bis(4-methoxyphenyl)-6-methylfuro[2,3-d]pyrimidine

Example 222 was prepared according to procedures similar to those shownin Scheme 1.

1H NMR (400 MHz, CDCl3) ppm 2.42–2.33 (br, 3H), 3.80 (s, 3H), 3.84 (s,3H), 6.87 (d, J=9.0 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 7.32–7.38 (m, 4H);HPLC: RT 3.30 min, LC/MS: m/z 362 (M+1)⁺, 360 (M−1)⁻. Example 223

4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)-6-(methylamino)furo[2,3-d]pyrimidine

Example 223 was prepared according to procedures similar to those shownin Scheme 4.

1H NMR (400 MHz, CDCl3) ppm 2.78 (d, J=4.8 Hz, 3H), 6.59 (m, 1H),7.38–7.43 (m, 3H), 7.48 (s, 1H), 7.48–7.53 (m, 1H), 7.60 (d, J=8.6 Hz,2H), 8.62 (dd, J=2.0 Hz, 7.3 Hz, 1H), 9.04 (brs, 1H), 9.42 (brs, 1H);LC/MS: m/z 461 (M+1)⁺, 459 (M−1)⁻.

Example 2244-Amino-3-(4-((2-naphthylsulfonyl)amino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 224 was prepared according to procedures similar to those shownin Example 3.

HPLC: RT 3.37 min, LC/MS: m/z 523 (M+1)⁺, 521 (M−1)⁻.

Example 2254-Amino-3-(4-(3-acetamidophenyl)phenyl)-2-(3-sulfamoylphenyl)-furo[2,3-d]pyrimidine

Example 225 was prepared according to procedures similar to those shownin Example 5.

HPLC: RT 2.68 min.

Example 2264-Amino-3-(4-(aminocarbonylamino)phenyl)-2-(4-methoxyphenyl)-furo[2,3-d]pyrimidine

Example 226 was prepared according to procedures similar to those shownin Example 4.

1H NMR (400 Hz, DMSO-d6) ppm 3.75 (s, 3H), 5.97 (s, 2H), 6.94 (d, J=9.1Hz, 2H), 7.33 (d, J=8.6 Hz, 2H), 7.40 (d, J=8.8 Hz, 2H), 7.59 (d, J=8.6Hz, 2H), 8.23 (s, 1H), 8.79 (s, 1H); HPLC: RT 2.65 min, LC/MS: m/z 376(M+1)⁺, 374 (M−1)⁻.

Example 2274-Amino-2-(4-methoxyphenyl)-3-(4-(phenyl(aminocarbonylamino))-phenyl)furo[2,3-d]pyrimidine

Example 227 was prepared according to procedures similar to those shownin Example 4.

1H NMR (400 Hz, DMSO-d6) ppm 3.75 (s, 3H), 6.94–7.01 (m, 3H), 7.30 (t,J=7.6 Hz, 2H), 7.39–7.42 (m, 4H), 7.48 (d, J=7.6 Hz, 2H), 7.65 (d, J=8.6Hz, 2H), 8.24 (s, 1H), 8.79 (s, 1H), 8.79 (s, 1H); HPLC: RT 3.21 min,LC/MS: m/z 452 (M+1)⁺, 450 (M−1)⁻.

Example 2284-Amino-3-(4-(cyclohexyl(aminocarbonylamino))phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 228 was prepared according to procedures similar to those shownin Example 4.

HPLC: RT 3.24 min.

Example 2294-Amino-3-(4-(butyl(aminocarbonylamino))phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 229 was prepared according to procedures similar to those shownin Example 4.

HPLC: RT 3.09 min.

Example 2304-Amino-3-(4-(((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)methyl)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 230 was prepared according to procedures similar to those shownin Example 4.

1H NMR (400 Hz, DMSO-d6) ppm 3.75 (s, 3H), 4.46 (s, 2H), 6.93 (d, J=9.1Hz, 2H), 7.32–7.50 (m, 9H), 8.25 (s, 1H), 8.63–8.66 (m, 1H), 8.88 (s,1H); HPLC: RT 3.48 min, LC/MS: m/z 552 (M+1)⁺, 550 (M−1)⁻.

Example 2314-Amino-3-(3-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 231 was prepared according to procedures similar to those shownin Example 4.

1H NMR (400 Hz, DMSO-d6) ppm 3.75 (s, 3H), 6.95 (d, J=9.0 Hz, 2H), 7.13(d, J=7.6 Hz, 1H), 7.40–7.58 (m, 6H), 7.65 (s, 1H), 8.25 (s, 1H), 8.56(d, J=6.3 Hz, 1H), 9.00 (s, 1H), 9.44 (s, 1H); HPLC: RT 3.59 min, LC/MS:m/z 538 (M+1)⁺, 536 (M−1)⁻.

Example 232(a): (See Also Example 8(C) and Example 232(b))4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 232 was prepared according to procedures similar to those shownin Example 8.

1H NMR (400 MHz, DMSO-d6) ppm 7.39–7.42 (m, 1H), 7.47 (d, J=8.6 Hz, 2H),7.49–7.54 (m, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.95 (s, 1H), 8.26 (s, 1H),8.63 (d, J=7.1 Hz, 1H), 8.99 (s, 1H), 9.39 (s, 1H); HPLC: RT 3.19 min,LC/MS: m/z 432 (M+1)⁺, 430 (M−1)⁻.

Example 2334-Amino-3-(4-(aminomethyl)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 233 was prepared according to procedures similar to those shownin Example 2.

HPLC: RT 2.47 min.

Example 2344-Amino-3-(3-aminophenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 234 was prepared according to procedures similar to those shownin Example 2.

HPLC: RT 2.88 min.

Example 2354-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)-2-(3-sulfamoylphenyl)furo[2,3-d]pyrimidine

Example 235 was prepared according to procedures similar to those shownin Example 8.

HPLC: RT 3.11 min, LC/MS: m/z 587 (M+1)⁺, 585 (M−1)⁻.

Example 2364-Amino-2-(4-cyanophenyl)-3-(4-((2-fluoro-5-(trifluoromethyl)-phenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 236 was prepared according to procedures similar to those shownin Example 8.

1H NMR (400 MHz, DMSO-d6) ppm 7.41–7.45 (m, 1H), 7.47 (d, J=8.6 Hz, 2H),7.53 (dd, J=9.2 Hz, 10.5 Hz, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.70 (d, J=8.6Hz, 2H), 7.84 (d, J=8.6 Hz, 2H), 8.31 (s, 1H), 8.64 (dd, J=2.0 Hz, 7.3Hz, 1H), 9.03 (brs, 1H), 9.48 (brs, 1H); HPLC: RT 3.52 min, LC/MS: m/z533 (M+1)⁺, 531 (M−1)⁻.

Example 2374-Amino-3-(4-(phenyl(aminothiocarbonylamino))phenyl)furo[2,3-d]pyrimidine

Example 237 was prepared according to procedures similar to those shownin Example 8.

HPLC: RT 2.78 min, LC/MS: m/z 362 (M+1)⁺, 360 (M−1)⁻.

Example 238 3-(4-nitrophenyl)-4-(phenylamino)furo[2,3-d]pyrimidine

Example 238 was prepared according to procedures similar to those shownin Scheme 4.

HPLC: RT 3.39 min, LC/MS: m/z 333 (M+1)⁺, 331 (M−1)⁻.

Example 239 4-(methyllamino)-3-(4-nitrophenyl)-furo[2,3-d]pyrimidine

Example 239 was prepared according to procedures similar to those shownin Scheme 4.

HPLC: RT 2.96 min, LC/MS: m/z 271 (M+1)⁺.

Example 240 3-(4-Aminophenyl)-4-(methylamino)furo[2,3-d]pyrimidine

Example 240 was prepared according to procedures similar to those shownin Scheme 4.

HPLC: RT 2.60 min, LC/MS: m/z 241 (M+1)⁺.

Example 241 3-(4-Aminophenyl)-4-(phenylamino)furo[2,3-d]pyrimidine

Example 241 was prepared according to procedures similar to those shownin Scheme 4.

HPLC: RT 3.21 min, LC/MS: m/z 303 (M+1)⁺.

Example 242 3-(4-Aminophenyl)-4-(dimethylamino)furo[2,3-d]pyrimidine

Example 242 was prepared according to procedures similar to those shownin Scheme 4.

HPLC: RT 2.77 min, LC/MS: m/z (M+1)⁺.

Example 243 4-(Dimethylamino)-3-(4-nitrophenyl)furo[2,3-d]pyrimidine

Example 243 was prepared according to procedures similar to those shownin Scheme 4.

HPLC: RT 3.14 min, LC/MS: m/z 285 (M+1)⁺.

Example 2443-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-phenyl)-4-(methylamino)furo[2,3-d]pyrimidine

Example 244 was prepared according to procedures similar to those shownin Scheme 4.

1H NMR (400 MHz, DMSO-d6) ppm 2.94 (d, J=4.8 Hz, 3H), 5.99–6.01 (m, 1H),7.39–7.45 (m, 3H), 7.52 (dd, J=8.8 Hz, 10.4 Hz, 1H), 7.63 (d, J=8.6 Hz,2H), 7.92 (s, 1H), 8.34 (s, 1H), 8.64 (dd, J=2.3 Hz, 7.3 Hz, 1H), 8.98(brs, 1H), 9.37 (brs, 1H); HPLC: RT 3.35 min, LC/MS: m/z 446 (M+1)⁺.

Example 2453-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-phenyl)-4-(phenylamino)furo[2,3-d]pyrimidine

Example 245 was prepared according to procedures similar to those shownin Scheme 4.

1H NMR (400 MHz, DMSO-d6) ppm 7.07 (m, 1H), 7.33 (m, 2H), 7.40–7.43 (m,1H), 7.52 (dd, J=9.4 Hz, 10.4 Hz, 1H), 7.56–7.60 (m, 4H), 7.66 (d, J=8.6Hz, 2H), 7.91 (brs, 1H), 8.13 (s, 1H), 8.49 (s, 1H), 8.63 (dd, J=2.3 Hz,7.3 Hz, 1H), 9.00 (brs, 1H), 9.40 (brs, 1H); HPLC: RT 3.72 min, LC/MS:m/z 508 (M+1)⁺, 506 (M−1)⁻.

Example 2464-(Dimethylamino)-3-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 246 was prepared according to procedures similar to those shownin Scheme 4.

1H NMR (400 MHz, DMSO-d6) ppm 2.82 (s, 6H), 7.39–7.43 (m, 3H), 7.52 (dd,J=9.1 Hz, 10.6 Hz, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.99 (s, 1H), 8.36 (s,1H), 8.63 (dd, J=2.3 Hz, 7.3 Hz, 1H), 8.99 (brs, 1H), 9.36 (brs, 1H);HPLC: RT 3.48 min, LC/MS: m/z 460 (M+1)⁺, 458 (M−1)⁻.

Example 247 4,5-Dihydro-3-(4-nitrophenyl)-4-oxofuro[2,3-d]pyrimidine

Example 247 was prepared according to procedures similar to those shownin Scheme 4.

HPLC: RT 2.77 min, LC/MS: m/z 256 (M−1)⁻.

Example 2483-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-phenyl)-6-(methylthio)furo[2,3-d]pyrimidine

Example 248 was prepared according to procedures similar to those shownin Scheme 4.

1H NMR (400 MHz, DMSO-d6) ppm 2.61 (s, 3H), 7.39–7.42 (m, 1H), 7.52 (dd,J=9.4 Hz, 10.1 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 7.79 (d, J=8.6 Hz, 2H),8.48 (s, 1H), 8.62 (dd, J=2.3 Hz, 7.3 Hz, 1H), 8.97 (brs, 1H), 9.36 (s,1H), 9.38 (brs, 1H); HPLC: RT 3.69 min, LC/MS: m/z 463 (M+1)⁺, 461(M−1)⁻.

Example 2494-Amino-3-(4-((3-ethylphenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 249 was prepared according to procedures similar to those shownin Example 8(C).

HPLC: RT 3.08 min, LC/MS: m/z 374 (M+1)⁺.

Example 2504-Amino-3-(4-((4-(dimethylamino)phenyl)aminocarbonylamino)-phenyl)furo[2,3-d]pyrimidine

Example 250 was prepared according to procedures similar to those shownin Example 8(C).

HPLC: RT 2.86 min, LC/MS: m/z 389 (M+1)⁺, 387 (M−1)⁻.

Example 2513-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-phenyl)-6-(methylsulfonyl)furo[2,3-d]pyrimidine

Example 251 was prepared according to procedures similar to those shownin Example 8(C).

1H NMR (400 MHz, DMSO-d6) ppm 3.48 (s, 3H), 7.41–7.44 (m, 1H), 7.52 (dd,J=9.5 Hz, 10.2 Hz, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.87 (d, J=8.6 Hz, 2H),8.63 (dd, J=2.2 Hz, 7.5 Hz, 1H), 8.91 (s, 1H), 8.99 (m, 1H), 9.43 (brs,1H), 9.77 (s, 1H); HPLC: RT 3.32 min, LC/MS: m/z 495 (M+1)⁺, 493 (M−1)⁻.

Example 2524-Amino-3-(4-((4-methoxyphenyl)aminocarbonylamino)phenyl)-furo[2,3-d]pyrimidine

Example 252 was prepared according to procedures similar to those shownin Example 8(C).

1H NMR (400 MHz, DMSO-d6) ppm 6.88 (d, J=9.1 Hz, 2H), 7.37 (d, J=9.1 Hz,2H), 7.42 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 7.92 (s, 1H), 8.25(s, 1H), 8.56 (brs, 1H), 8.81 (brs, 1H); HPLC: RT 2.82 min, LC/MS: m/z376 (M+1)⁺.

Example 2534-Amino-3-(4-((2,2,4,4-tetrafluoro-1,3-benzodioxan-5-yl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 253 was prepared according to procedures similar to those shownin Example 8(C).

HPLC: RT 3.28 min, LC/MS: m/z 476 (M+1)⁺, 474 (M−1)⁻.

Example 2544-Amino-3-(4-((4-(phenyloxy)phenyl)aminocarbonylamino)phenyl)-furo[2,3-d]pyrimidine

Example 254 was prepared according to procedures similar to those shownin Example 8(C).

HPLC: RT 3.20 min, LC/MS: m/z 438 (M+1)⁺.

Example 2554-Amino-3-(4-((5-Indanyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 255 was prepared according to procedures similar to those shownin Example 8(C).

1H NMR (400 MHz, DMSO-d6) ppm 1.97–2.04 (m, 2H), 2.78–2.85 (m, 4H),7.11–7.17 (m, 2H), 7.40–7.43 (m, 3H), 7.60 (d, J=8.6 Hz, 2H), 7.92 (s,1H), 8.25 (s, 1H), 8.61 (brs, 1H), 8.83 (brs, 1H); HPLC: RT 3.11 min,LC/MS: m/z 386 (M+1)⁺.

Example 2564-Amino-3-(4-((2,5-bis(trifluoromethyl)phenyl)aminocarbonylamino)-phenyl)furo[2,3-d]pyrimidine

Example 256 was prepared according to procedures similar to those shownin Example 8(C).

HPLC: RT 3.38 min, LC/MS: m/z 482 (M+1)⁺, 480 (M−1)⁻.

Example 2574-Amino-3-(4-((3-(phenyloxy)phenyl)aminocarbonylamino)phenyl)-furo[2,3-d]pyrimidine

Example 257 was prepared according to procedures similar to those shownin Example 8(C).

HPLC RT 3.23 min, LC/MS: m/z 438 (M+1)⁺, 436 (M−1)⁻.

Example 2584-Amino-3-(4-((2,5-dimethoxyphenyl)aminocarbonylamino)phenyl)-furo[2,3-d]pyrimidine

Example 258 was prepared according to procedures similar to those shownin Example 8(C).

HPLC: RT 2.95 min, LC/MS: m/z 406 (M+1)⁺, 404 (M−1)⁻.

Example 2594-Amino-3-(4-((5-(trifluoromethyl)phenyl)aminocarbonylamino)-phenyl)furo[2,3-d]pyrimidine

Example 251 was prepared according to procedures similar to those shownin Example 8(C).

1H NMR (400 MHz, DMSO-d6) ppm 7.32 (d, J=7.6 Hz, 2H), 7.45 (d, J=8.4 Hz,2H), 7.53 (dd, J=7.8 Hz, 1H), 7.59–7.64 (m, 3H), 7.94 (s, 1H), 8.04(brs, 1H), 8.26 (s, 1H), 9.02 (brs, 1H), 9.13 (brs, 1H); HPLC: RT 3.13min, LC/MS: m/z 414 (M+1)⁺, 412 (M−1)⁻.

Example 2604-Amino-3-(4-((5-(trifluoromethylthio)phenyl)aminocarbonylamino)-phenyl)furo[2,3-d]pyrimidine

Example 260 was prepared according to procedures similar to those shownin Example 8(C).

1H NMR (400 MHz, DMSO-d6) ppm 7.32 (d, J=7.8 Hz, 1H), 7.44–7.48 (m, 3H),7.56–7.57 (m, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.94 (s, 1H), 8.01 (brs, 1H),8.25 (s, 1H), 8.98 (brs, 1H), 9.07 (brs, 1H); HPLC: RT 3.25 min, LC/MS:m/z 446 (M+1)⁺, 444 (M−1)⁻.

Example 2614-Amino-3-(4-((3,4-(methylenedioxy)phenyl)aminocarbonylamino)-phenyl)furo[2,3-d]pyrimidine

Example 261 was prepared according to procedures similar to those shownin Example 8(C).

HPLC: RT 2.81 min, LC/MS: m/z 390 (M+1)⁺.

Example 2623-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-phenyl)-6-(methylamino)furo[2,3-d]pyrimidine

Example 262 was prepared according to procedures similar to those shownin Scheme 4.

1H NMR (400 MHz, DMSO-d6) ppm 2.85–2.86 (br, 3H), 7.40–7.42 (m, 1H),7.51 (dd, J=9.0 Hz, 10.5 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.8Hz, 2H), 8.08 (s, 1H), 8.63 (dd, J=2.2 Hz, 7.2 Hz, 1H), 8.93 (brs, 1H),8.98 (brs, 1H), 9.33 (brs, 1H); HPLC: RT 3.41 min, LC/MS: m/z 446(M+1)⁺, 444 (M−1)⁻.

Example 2636-((2-(Dimethylamino)ethyl)amino)-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 263 was prepared according to procedures similar to those shownin Scheme 4.

HPLC: RT 3.16 min, LC/MS: m/z 503 (M+1)⁺.

Example 2644-Amino-3-(4-((2-chlorophenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 264 was prepared according to procedures similar to those shownin Example 8(C).

1H NMR (400 MHz, DMSO-d6) ppm 7.05 (m, 1H), 7.32 (m, 1H), 7.45–7.49 (m,3H), 7.63 (d, J=8.6 Hz, 2H), 7.94 (s, 1H), 8.18 (dd, J=1.5 Hz, 8.3 Hz,1H), 8.25 (s, 1H), 8.38 (brs, 1H), 9.59 (brs, 1H); HPLC: RT 3.03 min,LC/MS: m/z 380 (M+1)⁺, 382 (M+3)⁺, 378 (M−1)⁺, 380 (M+1)⁻.

Example 2654-Amino-3-(4-((2-chloro-5-nitrophenyl)aminocarbonylamino)-phenyl)furo[2,3-d]pyrimidine

Example 265 was prepared according to procedures similar to those shownin Example 8(C).

HPLC: RT 3.09 min, LC/MS: m/z 425 (M+1)⁺, 427 (M+3)⁺, 423 (M−1)⁻.

Example 2664-Amino-3-(4-((3-chlorophenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 266 was prepared according to procedures similar to those shownin Example 8(C).

HPLC: RT 3.05 min, LC/MS: m/z 380 (M+1)⁺, 382 (M+3)⁺, 378 (M−1)⁺, 380(M+1)⁻.

Example 2674-Amino-3-(4-((2-chloro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 267 was prepared according to procedures similar to those shownin Example 8(C).

1H NMR (400 MHz, DMSO-d6) ppm 7.40 (dd, J=1.8 Hz, 8.1 Hz, 1H), 7.48 (d,J=8.6 Hz, 2H), 7.64 (d, J=8.6 Hz, 2H), 7.74 (d, J=8.1 Hz, 1H), 7.95 (s,1H), 8.26 (s, 1H), 8.66 (d, J=2.0 Hz, 2H), 8.68 (s, 1H), 9.75 (s, 1H);HPLC: RT 3.29 min. LC/MS: m/z 448 (M+1)⁺, 450 (M+3)⁺, 446 (M−1)⁺, 448(M+1)⁻.

Example 2684-Amino-3-(4-((2,5-dichlorophenyl)aminocarbonylamino)phenyl)-furo[2,3-d]pyrimidine

Example 268 was prepared according to procedures similar to those shownin Example 8(C).

1H NMR (400 MHz, DMSO-d6) ppm 7.12 (dd, J=2.5 Hz, 8.6 Hz, 1H), 7.47 (d,J=8.6 Hz, 2H), 7.52 (d, J=8.6 Hz, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.95 (s,1H), 8.26 (s, 1H), 8.34 (d, J=2.5 Hz, 1H), 8.53 (s, 1H), 9.71(s, 1H);HPLC: RT 3.25 min, LC/MS: m/z 414 (M)⁺, 416(M+2)⁺, 412 (M−2)⁺, 414 (M)⁻.

Example 2693-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)-phenyl)-6-(((2,4,6-trimethoxyphenyl)methyl)amino)furo[2,3-d]pyrimidine

Example 269 was prepared according to procedures similar to those shownin Scheme 4.

HPLC: RT 3.72 min, LC/MS: m/z 612 (M+1)⁺.

Example 2706-Amino-3-(4-((2-Fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 270 was prepared according to procedures similar to those shownin Scheme 4.

1H NMR (400 MHz, DMSO-d6) ppm 6.88 (s, 2H), 7.39–7.43 (m, 1H), 7.51 (dd,J=9.0 Hz, 10.5 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H),8.08 (s, 1H), 8.63 (dd, J=2.3 Hz, 7.3 Hz, 1H), 8.94 (s, 1H), 8.96 (brs,1H), 9.35 (brs, 1H); HPLC: RT 3.23 min, LC/MS: m/z 432 (M+1)⁺.

Example 2714-Amino-3-(4-aminophenyl)-6-(methylthio)furo[2,3-d]pyrimidine

Example 271 was prepared according to procedures similar to those shownin Scheme 4.

1H NMR (400 MHz, DMSO-d6) ppm 2.47 (s, 3H), 5.34 (s, 2H), 6.67 (d, J=8.6Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 7.66 (s, 1H); HPLC: RT 2.91 min. LC/MS:m/z 273 (M+1)⁺.

Example 272: (Example 8(D))4-Amino-2-bromo-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 272 was prepared according to procedures similar to those shownin Example 8.

1H NMR (400 MHz, DMSO-d6) ppm 7.40–7.43 (m, 1H), 7.45 (d, J=8.6 Hz, 2H),7.52 (dd, J=8.8 Hz, 10.9 Hz, 1H), 7.66 (d, J=8.6 Hz, 2H), 8.24 (s, 1H),8.64 (d, J=7.1 Hz, 1H), 9.00 (s, 1H), 9.41 (s, 1H); LC/MS: m/z 510 (M)⁺,512 (M+2)⁺.

Example 2734-Amino-3-(4-((4-tert-butylthiazol-2-yl)aminocarbonylamino)-phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine

Example 273 was prepared according to procedures similar to those shownin Example 8(C).

1H NMR (400 MHz, DMSO-d6) ppm 1.27 (s, 9H), 3.75 (s, 3H), 6.67 (s, 1H),6.95 (m, 2H), 7.42 (m, 4H), 7.65 (m, 2H), 8.24 (s, 1H), 9.10 (br, 1H),10.72 (br, 1H); LC/MS: m/z 515 (M+1)⁺.

Example 2744-Amino-3-(4-((2-thienyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 274 was prepared according to procedures similar to those shownin Example 8(C).

1H NMR (400 MHz, DMSO-d6) ppm 6.58 (m, 1H), 6.82 (m, 1H), 6.89 (m, 1H),7.44 (m, 2H), 7.62 (m, 2H), 7.93 (s, 1H), 8.25 (s, 1H), 8.97 (br, 1H),9.74 (br, 1H); LC/MS: m/z 352 (M+1)⁺,

Example 2754-Amino-2-bromo-3-(4-((5-indanyl)aminocarbonylamino)phenyl)-furo[2,3-d]pyrimidine

Example 275 was prepared according to procedures similar to those shownin Example 8(C).

1H NMR (400 MHz, DMSO-d6) ppm 2.01 (m, 2H), 2.82 (m, 4H), 7.15 (m, 2H),7.41 (m, 3H), 7.64 (m, 2H), 8.24 (s, 1H), 8.72 (br, 1H), 8.97(br, 1H);LC/MS: m/z 464 (M) +, 466 (M+2)⁺.

Example 2764-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenyl)thieno[2,3-d]pyrimidine;

276(A): 1,1-dicyano-2-(4-nitro-phenyl)-propene

4Nitro acetophenone (2.0 g, 12.1 mmoles, 1 eq) and malonodinitrile (2.4g, 36.3 mmoles, 3 eq) were dissolved in 20 mL of anhydrous toluene. Tothe solution were added glacial acetic acid (0.40 mL, 7.0 mmoles, 0.19eq) and ammonium acetate (0.26 g, 3.3 mmoles, 0.09 eq). The system washeated to reflux using a Dean-Stark trap and a condenser. After 1 hour,the reaction mixture was cooled to room temperature and poured intobrine (50 mL) and ethyl acetate (100 mL). The aqueous layer was washedwith 3×10 mL ethyl acetate. The combined organic layers were washed with50 mL brine, dried over anhydrous sodium sulfate and concentrated todryness. The dark residue was partially purified using a silica plug(40% ethyl acetate-hexane) affording crude1,1-dicyano-2-(4-nitrophenyl)-propene. The product was used as such inthe next step. TLC (40% ethyl acetate-hexane)=0.61. LC-MS (m/e)=214.2(MH+).

276(B): 1-amino-2-cyano-3-(4-nitro-phenyl) thiophene

1,1-Dicyano-2-(4-nitrophenyl)-propene (0.97 g crude, 4.55 mmolesassumed, 1 eq) was dissolved in 12 mL DMF, treated with sulfur (0.44 g,13.8 mmoles, 3 eq) and heated to 120° C. for 10 minutes. The system wascooled to room temperature and poured into brine (20 mL) and methylenechloride (50 mL). The aqueous layer was washed with methylene chloride(2×10 mL). The organic layers were combined, dried over anhydrous sodiumsulfate and concentrated to dryness. The residue was agitated in 20 mLmethylene chloride; excess sulfur separated and was removed byfiltration. The resulting solution was concentrated to dryness andpurified by column chromatography (40% ethyl acetate-hexane) to afford1-amino-2-cyano-3-(4-nitro-phenyl) thiophene. ¹H-NMR (CDCl3): δ 5.0 (2H,br), 6.6 (1H, s), 8.1 (2H, d, J=8.8 Hz), 8.3 (2H, d, J=8.8 Hz). LC-MS(m/e)=246.0 (MH+). TLC (40% ethyl acetate-hexane)=0.44.

276(C): 5-(4-nitro-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine

1-Amino-2-cyano-3-(4-nitro-phenyl) thiophene (250 mg, 1.02 mmoles) washeated to reflux in 5 mL formamide. The system was cooled to roomtemperature and poured into 20 mL methylene chloride and 20 mL brine.The organic layer was washed with 10 mL brine. The aqueous layers werecombined and extracted with 3×10 mL methylene chloride. The organiclayers were combined, dried over anhydrous sodium sulfate, andconcentrated to dryness under vacuum, yielding a yellow solid residue.This solid was dissolved in methanol, treated with 1.5 g silica gel andconcentrated to dryness under vacuum. The resulting solid was loadedonto a silica gel column pre-equilibrated with 80% ethyl acetate-hexaneand eluted with 80% ethyl acetate-hexane, to afford5-(4-nitro-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine. ¹H-NMR (CDCl₃): δ4.9 (2H, br), 6.9 (1H, s), 7.2 (1H, s), 7.6 (2H, d, J=8.8 Hz), 8.4 (2H,d, J=8.8 Hz). LC-MS (m/e)=273.0 (MH+). TLC (100% ethyl acetate)=0.63.

276 (D): 5-(4-amino-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine

5-(4-Nitro-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine (50 mg, 0.18 mmoles,1 eq) was suspended in 5 mL aqueous HCl 6N and treated with tin (100 mg,0.90 mmoles, 5 eq). TLC (100% ethyl acetate) indicated that the reactionwas complete after 30 minutes. The system was basified with NH₄OH (conc)to pH 10 and treated with 20 mL brine and 20 mL CH₂Cl₂. The aqueouslayer was back-extrated with 3×10 mL CH₂Cl₂. All organic layers werecombined, washed with 30 mL brine, dried over anhydrous sodium sulfateand concentrated to dryness. The residue was dissolved in minimal amountof methylene chloride, filtered and concentrated to dryness. Theresulting 5-(4-amino-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine was usedas such in the next step. TLC (100% ethyl acetate)=0.58. LC-MS(m/e)=243.0 (MH+).

276 (E):1-[4-(4-Amino-thieno[2,3-d]pyrimidin-5-yl)-phenyl]-3-(2-fluoro-5-trifluoromethyl-phenyl)-urea

5-(4-Amino-phenyl)-thieno[2,3-d]pyrimidin-4-ylamine (0.18 mmoles) wasdissolved in 6 mL anhydrous THF and treated with 510 μL of a 0.35 M THFsolution of 2-fluoro-5-trifluoromethyl-phenyl isocyanate (0.18 mmoles, 1eq). After 30 minutes, the solution was treated with 2 mL methanol and 1mL triethylamine, stirred for 30 minutes and concentrated to drynessunder vacuum. The residue was purified by preparative HPLC to afford thetitlecompound:1-[4-(4-amino-thieno[2,3-d]pyrimidin-5-yl)-phenyl]-3-(2-fluoro-5-trifluoromethyl-phenyl)-urea.¹H-NMR (DMSO-d6): δ 7.2 (2H, d, J=8.8 Hz), 7.3 (1H, s), 7.4 (2H, d,J=8.8 Hz), 8.2 (1H, br), 8.4 (1H, br), 8.8 (1H, s), 9.2 (1H, br). TLC(80% ethyl acetate-hexane)=0.48. LC-MS (m/e)=448.2.0 (MH+).

Example 2774-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonyl-amino)phenyl)-6-(((2,4,6-trimethoxyphenyl)methyl)amino)furo[2,3-d]pyrimidine

Example 277 was prepared according to procedures similar to those shownin Scheme 4.

1H NMR (400 MHz, DMSO-d6) ppm 3.78 (s, 3H), 3.78 (s, 6H), 4.38 (d, J=5.1Hz, sH), 5.78 (m, 1H), 6.00 (br, 2H), 6.25 (s, 2H), 7.39–7.42 (m, 1H),7.43 (d, J=7.34 Hz, 2H), 7.49–7.54 (m, 1H), 7.50 (s, 1H), 7.60 (d,J=8.59 Hz), 8.63 (dd, J=2.0 Hz, 7.33 Hz), 8.97 (brs, 1H), 9.35 (brs,1H);

LC/MS: m/z 627 (M+1)⁺, 625 (M−1)⁻.

Example 2784-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)-2-(3-pyridyl)furo[2,3-d]pyrimidine

Example 278 was prepared according to procedures similar to those shownin Example 8.

1H NMR (400 MHz, DMSO-d6) ppm 7.40–7.45 (m, 2H), 7.46 (d, J=8.6 Hz, 2H),7.52 (dd, J=9.3 Hz, 10.4 Hz, 1H), 7.69 (d, J=8.6 Hz, 2H), 7.84 (ddd,J=1.9 Hz, 1.9 Hz, 8.3 Hz, 1H), 8.30 (s, 1H), 8.51 (dd, J=1.5 Hz, 4.8 Hz,1H), 8.60 (d, J=2.3 Hz, 1H), 8.63 (dd, J=2.1 Hz, 7.2 Hz, 1H), 9.07 (brs,1H), 9.50 (brs, 1H);

LC/MS: m/z 509 (M+1)⁺, 507 (M−1)⁻.

Example 2794-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)-2-vinylfuro[2,3-d]pyrimidine

Example 279 was prepared according to procedures similar to those shownin Example 8.

1H NMR (400 MHz, DMSO-d6) ppm 5.44 (d, J=12.6 Hz, 1H), 5.88 (d, J=17.3Hz, 1H), 6.57 (dd, J=11.4 Hz, 17.2 Hz, 1H), 7.40–7.42 (m, 1H), 7.41 (d,J=8.6 Hz, 2H), 7.52 (dd, J=9.1 Hz, 10.4 Hz, 1H), 7.67 (d, J=8.59, 2H),8.27 (s, 1H), 8.65 (dd, J=2.1 Hz, 7.20 Hz, 1H), 8.99 (brs, 1H), 9.42(brs, 1H);

LC/MS: m/z 458 (M+1)⁺, 456 (M−1)⁻.

Example 2804-Amino-2-(1,2-dihydroxyethyl)-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 280 was prepared according to procedures similar to those shownin Example 8.

1H NMR (400 MHz, DMSO-d6) ppm 3.67–3.70 (m, 2H), 4.54 (m, 1H), 7.93 (m,1H), 5.58 (m, 1H), 7.39–7.44 (m, 1H), 7.46 (d, J=8.6 Hz, 2H), 7.49–7.54(m, 1H), 7.64 (d, J=8.6 Hz, 2H), 8.24 (s, 1H), 8.63 (m, 1H), 9.02 (brs,1H), 9.41 (brs, 1H); LC/MS: m/z 492 (M+1)⁺, 490 (M−1)⁻.

Example 2814-Amino-2-carboxy-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 281 was prepared according to procedures similar to those shownin Example 8.

1H NMR (400 MHz, DMSO-d6) ppm 7.40–7.43 (m, 1H), 7.46 (d, J=8.6 Hz, 2H),7.50–7.54 (m, 1H), 7.61 (d, J=8.6 Hz, 2H), 8.35 (s, 1H), 8.64 (dd, J=2.0Hz, 7.3 Hz, 1H), 9.00 (brs, 1H), 9.40(brs, 1H);

Example 2824-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)-2-iodofuro[2,3-d]pyrimidine

Example 282 was prepared according to procedures similar to those shownin Example 8.

1H NMR (400 MHz, DMSO-d6) ppm 7.41 (d, J=8.6 Hz, 2H), 7.52 (dd, J=9.5Hz, 9.7 Hz, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.95 (s, 1H), 8.18 (s, 1H),8.62 (d, J=6.8 Hz, 1H), 9.18 (brs, 1H), 7.59 (brs, 1H); LC/MS: m/z 492(M+1)⁺, 490 (M−1)⁻.

Example 2834-Amino-2-(4-carboxyphenyl)-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 283 was prepared according to procedures similar to those shownin Example 8.

1H NMR (400 MHz, DMSO-d6) ppm 7.40–7.44 (m, 1H), 7.46 (d, J=8.6 Hz, 2H),7.49–7.55 (m, 1H), 7.55 (d, J=8.3 Hz, 2H), 7.69 (d, J=8.6 Hz, 2H), 7.89(d, J=8.3 Hz, 2H), 8.29 (s, 1H), 8.62 (dd, J=2.1 Hz, 7.2 Hz, 1H), 9.07(brs, 1H), 9.51 (brs, 1H); LC/MS: m/z 552 (M+1)⁺, 550 (M−1)⁻.

Example 2844-Amino-2-carbamoyl-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 284 was prepared according to procedures similar to those shownin Example 8.

1H NMR (400 MHz, DMSO-d6) ppm 7.39–7.43 (m, 1H), 7.44 (d, J=8.8 Hz, 2H),7.49–7.54 (m, 1H), 7.59 (d, J=8.6 Hz, 2H), 7.90 (brs, 1H), 7.59 (brs,1H), 8.34 (s, 1H), 8.64 (dd, J=2.1 Hz, 7.2 Hz, 1H), 9.04 (brs, 1H), 9.43(brs, 1H);

LC/MS: m/z 475 (M+1)⁺, 473 (M−1)⁻.

Example 2854-Amino-2-(N-(carbamoylmethyl)carbamoyl)-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 285 was prepared according to procedures similar to those shownin Example 8.

1H NMR (400 MHz, DMSO-d6) ppm 3.74 (d, J=5.8 Hz, 2H), 7.04 (brs, 1H),7.40–7.54 (m, 5H), 7.59 (d, J=8.6 Hz, 2H), 8.34 (s, 1H), 8.57 (t, J=5.8Hz, 1H), 8.64 (dd, J=2.0 Hz, 7.3 Hz, 1H), 9.00 (brs, 1H), 9.43 (brs,1H); LC/MS: m/z 532 (M+1)⁺.

Example 2864-Amino-6-dimethylamino-3-(4-((2-fluoro-5-(trifluoromethyl)-phenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 286 was prepared according to procedures similar to those shownin Scheme 4.

1H NMR (400 MHz, DMSO-d6) ppm 3.09 (s, 6H), 6.06 (brs, 2H), 7.39–7.44(m, 3H), 7.52 (s, 1H), 7.49–7.54 (m, 1H), 7.60 (d, J=8.6 Hz, 2H), 8.63(dd, J=2.1 Hz, 7.2 Hz), 9.00 (brs, 1H), 9.37 (brs, 1H); LC/MS: m/z 475(M+1)⁺, 473 (M−1)⁻.

Example 2874-Amino-6-((2-(dimethylamino)ethyl)amino)-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 287 was prepared according to procedures similar to those shownin Scheme 4.

1H NMR (400 MHz, DMSO-d6) ppm 2.20 (s, 6H), 2.42 (t, J=6.7 Hz, 2H),2.46–2.53 (m, 2H), 6.43 (m, 1H), 7.38–7.44 (m, 1H), 7.41 (d, J=8.6 Hz,2H), 7.49 (s, 1H), 7.50–7.54 (m, 1H), 7.60 (d, J=8.6 Hz, 2H), 8.22 (s,1H), 8.63 (dd, J=2.0 Hz, 7.1 Hz, 1H), 9.03 (brs, 1H), 9.41 (brs, 1H);

Example 2884-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonyl-amino)phenyl)-6-((2-(methylsulfonylamino)ethyl)amino)furo[2,3-d]pyrimidine

Example 288 was prepared according to procedures similar to those shownin Scheme 4.

1H NMR (400 MHz, DMSO-d6) ppm 2.91 (s, 3H), 3.10–3.15 (m, 2H), 6.01(brs, 2H), 6.68 (m, 1H), 7.07 (m, 1H), 7.38–7.41 (m, 1H), 7.42 (d, J=8.6Hz, 2H), 7.51 (s, 1H), 7.48–7.53 (m, 1H), 7.60 (d, J=8.6 Hz, 2H), 8.62(dd, J=2.3 Hz, 7.1 Hz, 1H), 9.01 (brs, 1H), 9.38 (brs, 1H); LC/MS: m/z568 (M+1)⁺, 566 (M−1)⁻.

Example 2894-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonyl-amino)phenyl)-6-((3-(methylsulfinyl)propyl)amino)furo[2,3-d]pyrimidine

Example 289 was prepared according to procedures similar to those shownin Scheme 4.

1H NMR (400 MHz, DMSO-d6) ppm 1.85–1.93 (m, 2H), 2.53 (s, 3H), 2.66–2.73(m, 1H), 2.79–2.86 (m, 1H), 5.98 (brs, 2H), 6.81 (m, 1H), 7.39–7.42 (m,1H), 7.42 (d, J=8.6 Hz, 2H), 7.48–7.54 (m, 1H), 7.49 (s, 1H), 7.60 (d,J=8.8 Hz, 2H), 8.62 (dd, J=2.3 Hz, 7.1 Hz, 1H), 9.05 (brs, 1H), 9.43(brs, 1H); LC/MS: m/z 551 (M+1)⁺, 549 (M−1)⁻.

Example 2904-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonyl-amino)phenyl)-6-((3-(methylthio)propyl)amino)furo[2,3-d]pyrimidine

Example 290 was prepared according to procedures similar to those shownin Scheme 4.

1H NMR (400 MHz, DMSO-d6) ppm 1.75–7.82 (m, 2H), 2.05 (s, 3H), 6.77(brs, 1H), 7.39–7.41 (m, 1H), 7.42 (d, J=8.6 Hz, 2H), 7.50 (s, 1H),7.48–7.54 (m, 1H), 7.59 (d, J=8.6 Hz, 2H), 8.64 (dd, J=2.4 Hz, 7.2 Hz,1H), 9.00 (brs, 1H), 9.33 (brs, 1H); LC/MS: m/z 535 (M+1)⁺, 533 (M−1)⁻.

Example 2914-Amino-2-chloro-3-(4-((3-phenyl-1,2,4-thiadiazol-5-yl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

Example 291 was prepared according to procedures similar to those shownin Example 8(D).

1H NMR (400 MHz, DMSO-d6) ppm 7.49–7.53 (m, 6H), 7.71–7.73 (m, 2H), 7.97(s, 1H), 8.16–8.19 (m, 3H), 8.28 (s, 1H), 9.46 (s, 1H), 11.64 (s, 1H);HPLC: RT min, LC/MS: m/z 464 (M+1)⁺, 466 (M+3)⁺, 462 (M−2)⁻, 464 (M+1)⁻.

Example 2924-Amino-3-(4-((5-tert-butylisoxazol-3-yl)aminocarbonyl-amino)phenyl)furo[2,3-d]pyrimidine

Example 292 was prepared according to procedures similar to those shownin Example 8(C).

1H NMR (400 MHz, DMSO-d6) ppm 1.30 (s, 9H), 6.52 (s, 1H), 7.44–7.46 (m,2H), 7.59–7.62 (m, 2H), 7.94 (s, 1H), 8.25 (s, 1H), 9.00 (s, 1H), 9.58(s, 1H); HPLC: RT min, LC/MS: m/z 393 (M+1)⁺, 391 (M−1)⁻.

Example 2934-Amino-3-(4-((3-fluorobenzoyl)amino)phenyl)-2-(3-pyridyl)furo[2,3-d]pyrimidine

Example 293 was prepared according to procedures similar to those shownin Example 3.

1H NMR (400 MHz, DMSO-d6) ppm 7.42–7.53 (m, 4H), 7.53–7.65 (m, 1H),7.77–7.87 (m, 3H), 8.00–8.03 (m, 2H), 8.30 (s, 1H), 8.50–8.52 (m, 1H),8.59–8.60 (m, 1H), 10.57 (s, 1H); HPLC: RT min, LC/MS: m/z 426 (M+1)⁺,427 (M+2)⁺, 424 (M−1)^(−b, 425) (M)⁻.

Example 2944-Amino-3-(4-((4-fluorobenzenesulfonyl)amino)phenyl)-2-(3-pyridyl)furo[2,3-d]pyrimidine

Example 294 was prepared according to procedures similar to those shownin Example 3.

1H NMR (400 MHz, DMSO-d6) ppm 7.20–7.22 (m, 3H), 7.37–7.44 (m, 6H),7.72–7.80 (m, 1H), 7.81–7.83 (m, 2H), 8.27 (s, 1H), 8.45–8.51 (m, 2H),10.52 (s, 1H); HPLC: RT min, LC/MS: m/z 462 (M+1)⁺, 460 (M−1)⁻, 461(M)⁻.

Example 2954-Amino-2-(3-pyridyl)-3-(4-((2-thienylsulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine

Example 295 was prepared according to procedures similar to those shownin Example 3.

1H NMR (400 MHz, DMSO-d6) ppm 7.16–7.19 (m, 1H), 7.29–7.31 (m, 2H),7.38–7.45 (m, 3H), 7.57–7.59 (m, 1H), 7.70–7.74 (m, 1H), 7.93–7.95 (m,1H), 8.29 (s, 1H), 8.50–8.52 (m, 2H), 10.63 (s, 1H); HPLC: RT min,LC/MS: m/z 450 (M+1)⁺, 451 (M+2)⁺, 448 (M−1)⁻, 449 (M)⁻, 450 (M+1)⁻.

Example 2964-Amino-3-(4-((2,3-dichlorobenzenesulfonyl)amino)phenyl)-2-(3-pyridyl)furo[2,3-d]pyrimidine

Example 296 was prepared according to procedures similar to those shownin Example 3.

1H NMR (400 MHz, DMSO-d6) ppm 7.24–7.26 (m, 2H), 7.32–7.35 (m, 3H),7.38–7.41 (m, 2H), 7.56–7.60 (m, 1H), 7.62–7.66 (m, 1H), 7.96–7.99 (m,1H), 8.07–8.09 (m, 1H), 8.27 (s, 1H), 8.46–8.51 (m, 2H), 11.09 (s, 1H);HPLC: RT min, LC/MS: m/z 512 (M)⁺, 514 (M+2)⁺, 515 (M+3)⁺, 510 (M−2)⁻,512 (M)⁻, 514 (M+3)⁻.

Example 2974-Amino-2-(2-methoxypyridin-5-yl)-3-((4-(phenylsulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

Example 297 was prepared according to procedures similar to those shownin Example 3.

1H NMR (400 MHz, DMSO-d6) ppm 3.86 (s, 1H), 6.78–6.81 (m, 1H), 7.21–7.24(m, 2H), 7.35–7.38 (m, 2H), 7.57–7.68 (m, 4H), 7.75–7.79 (m, 2H), 8.08(br, 1H), 8.25 (s, 1H), 10.49 (s, 1H); HPLC: RT min, LC/MS: m/z 474(M+1)⁺, 476 (M+3)⁺, 472 (M−1)⁻, 473 (M)⁻, 474 (M+2)⁻.

Example 2984-Amino-2-(3-pyridyl)-3-((4-((1,2,3,4-tetrahydroisoquinolin-7-yl)sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

Example 298 was prepared according to procedures similar to those shownin Example 3.

1H NMR (400 MHz, DMSO-d6) ppm 2.68 (t, J=5.7 Hz, 2H), 2.92 (t, J=5.7 Hz,2H), 3.17 (d, J=4.3 Hz, 1H), 3.83 (s, 2H), 7.02–7.04 (m, 2H), 7.11–7.18(m, 3H), 7.36–7.40 (m, 2H), 7.43–7.46 (m, 1H), 7.78–7.82 (m, 1H), 8.26(s, 1H), 8.47–8.49 (m, 1H), 8.57–8.58 (m, 1H); HPLC: RT min, LC/MS: m/z499 (M+1)⁺, 500 (M+2)⁺, 501 (M+3)⁺, 497 (M−1)⁻, 498 (M)⁻, 499 (M+2)⁻.

Example 232(b) and Examples 299–479 are made according to the proceduresof Schemes 6–12 and Intermediate Examples 1–13.

The numerals 1 through 9 in the following examples refer to Scheme 6.

Intermediate Example 1 4′-Acetamido-acetophenone (2)

To a suspension of 4-aminoacetophenone 1 (74 g, 547 mmol) in toluene(700 mL), acetic anhydride (56 mL 593 mmol) was added dropwise at roomtemperature. Soon after added all of acetic anhydride, the reactionmixture became a clear solution and then rapidly began to make a whiteprecipitation. The precipitation were filtrated and washed with a smallamount of toluene then dried under reduced pressure to afford 2 as awhite solid (93 g, 960% yield): MS(ES) m/e 178 [M+H].

Intermediate Example 2 4′-Acetamido-2-bromoacetophenone (3)

To a suspension of 4′-acetamido-acetophenone 2 (21.84 g, 123 mmol) inacetic acid (184 mL), bromine (6.5 mL, 127 mmol) was added. The mixturewas heated (inner temp: 52° C., oil bath temp: 60˜65° C.) with vigorousstirring until the suspension make a clear solution. The heating bathwas rapidly removed, and the mixture was stirred at room temperature for15 min and then stirred in an ice-water bath for 2 h(inner temp. 50°C.˜20° C.). The precipitation was filtrated, washed with 30% EtOH inwater, and dried under reduced pressure to give 3 as a pale brown solid(24.0 g, 75% yield): MS(ES) m/e 257 [M+H].

Intermediate Example 3 4′-Acetamido-2-hydroxyacetophenone (4)

To a suspension of 4′-acetamido-2-bromoacetophenone 3 (10.0 g, 39 mmol)in EtOH (800 mL), aqueous potassium formate (35.4 g in 200 mL) was addedthen followed by sodium bicarbonate (3.68 g). The mixture was stirred at38° C. (inner temp.) for 22 h. The mixture was evaporated in vacuo untilthe total volume reached to ca. 300 mL The mixture was diluted withethyl acetate (1200 mL), washed with water (200 mL), then brine (2×400mL). Aqueous layers were extracted with ethyl acetate (800 mL then 400mL). Combined organic layer was dried over anhydrous sodium sulfate andthen evaporated in vacuo to give crude 4 as a solid (7.17 g, 95%) whichwas used to the next step without any purification. MS(ES) m/e 194[M+H].

Intermediate Example 4 4-(4-Acetamidophenyl)-2-amino-3-cyanofurane (5)

To a solution of 4′-acetamido-2-hydroxyacetophenone 4 (7.17 g, 39 mmol)in DMF (65 mL), malononitrile (2.84 g, 43 mmol) was added. With coolingin an ice-water bath, diethylamine (6.05 mL 59 mmol) was gradually addedwithin 20 min. The mixture was stirred at room temperature for 2 h andthen diluted with ethyl acetate (400 mL). The mixture was washed withbrine (3×200 mL), dried over sodium sulfate, and then evaporated invacuo. Residual material was treated with dichloromethane and n-hexane,concentrated in vacuo, and precipiated in the concentrated mixture. Theprecipitated material was filtrated and washed with n-hexane to give 5(7.64 g) as a brown solid. MS(ES) m/e 242 [M+H].

Intermediate Example 54-(4-Acetamidophenyl)-3-cyano-2-[(ethoxymethylidene)amino]furane (6)

Method A (by Means of Triethyl Orthoformate)

To a suspension of 4-(4-acetamidophenyl)-2-amino-3-cyanofurane 5 (7.64g, 39 mmol) in triethyl orthoformate (306 mL), acetic anhydride (15 mL)was added at room temperature. The mixture was heated (inner temp: 100°C.) in an oil bath for 1 h. The black material was precipitated in themixture and then filtrated. The filtrated material was purified on asilica gel column (eluted by n-hexane-EtOAc 1:3) to afford 473 mg of 6as a yellow solid. The filtered solution was concentrated in vacuo toafford 6 (7.44 g) as a dark orange solid.

Method B (by Means of Diethoxymethyl Acetate)

At room temperature, to the mixture of4-(4-acetamidophenyl)-2-amino-3-cyanofurane 5 (6.0 g, 25 mmol) in aceticacid (60 mL), diethoxymethyl acetate (41 mL, 25 mmol) was addeddropwise. The mixture was stirred at room temperature for 30 min andthen concentrated (below 40° C. in water bath). The residual paste wasdried up with a pump. The dried solid material was triturated with etherthen filtrated to afford 6 (3.93 g) as a solid. MS(ES) m/e 298 [M+H].

Intermediate Example 64-(4-Acetamidophenyl)-2-[(aminomethylidene)amino]-3-cyanofurane (7)

A suspension of 4-(4-acetamidophenyl)-3-cyano-2-[(ethoxymethylidene)amino]furane 6 (1.12 g, 3.76 mmol) in a mixture of EtOH (40 mL) and THF(40 mL) was chilled in an ice-water bath. Into the mixture with vigorousstirring, NH3 gas was bubbled for 25 min. The suspension was oncedissolved and then it began to make a precipitation. The mixture in atightly closed flask was stirred at room temperature for 3 h. Themixture was evaporated in vacuo to give 7 (1.1 g) as a brown solid whichwas used for the next step without any purification. MS(ES) m/e 269[M+H].

Intermediated Example 73-(4-Acetamidophenyl)-4-aminofuro[2,3-d]pyrimidine (8)

The crude4-(4-Acetamidophenyl)-2-[(aminomethylidene)amino]-3-cyanofurane 7obtained from the last step was suspended in the mixture of EtOH(30 mL)and THF (30 mL). To the suspension was added dropwise 5 mL (0.8N, 4mmol) of sodium ethoxide (freshly prepared ethanol solution) within 5min. The suspended material was gradually dissolved with stirring atroom temperature. After stirred for 4 h, the mixture was concentrated invacuo to obtain ca. 15 mL of a residual solution. The solution wasdiluted with ethyl acetate (200 mL), washed with brine (×2), and driedover anhydrous sodium sulfate. The mixture was concentrated and driedunder reduced pressure to give 8 (0.92 g) as a brown solid. MS(ES) m/e269 [M+H].

Intermediate Example 8 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine(9)

Compound 3-(4-acetamidophenyl)-4-aminofuro[2,3-d]pyrimidine 8 (242 mg)was dissolved in 2 M potassium hydroxide in the mixture of EtOH (16 mL)and water (4 mL). The mixture was heated (60° C.) for 24 h thenconcentrated in vacuo. Residual oil was triturated with cold water (6mL) to give precipitation, which was filtrated, washed with water, anddried under the reduced pressure. The compound 9 (118 mg) as pale orangecolored was obtained. MS(ES) m/e 227M+H].

Example 232(b)4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

To compound 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) (1 g 4.42mmol) in THF (50 mL), 2-fuoro-5-(trifluoromethyl)-phenyl isocyanate (0.7mL, 4.86 mmol) was added in one portion. After the mixture was stirredat room temperature for 2 h, the solvent was evaporated. The residue waspurified by column. (1:1 EtOAc/hexane–9:1 EtOAc/hexane) to afford thedesired product. MS(ES) m/e 432 [M+H].

Example 2994-Amino-3-(4-((2-fluoro-5-methoxyphenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example232(b), using 2-fluoro-5-methoxyphenyl isocyanate as the isocyanate ofchoice, and 4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as thediamine of choice. MS(ES) m/e 394 [M+H]+.

Intermediate Example 9 4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine(10)

The compound was prepared following the procedures described in making4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9), using3-aminoacetophenone instead of 4-aminoacetophenone as starting material.MS(ES) m/e 227 [M+H]⁺.

Example 3004-Amino-3-(3-((4-chlorophenyl)aminocarbonylamino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described Example232(b), using 4-chlorophenyl isocyanate as the isocyanate of choice and4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine ofchoice. MS(ES) m/e 380 [M+H]⁺.

Example 3014-Amino-3-(3-((phenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example232(b), using phenyl isocyanate as the isocyanate of choice, and4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine ofchoice. MS(ES) m/e 346 [M+H]⁺.

Example 3024-Amino-3-(3-((cyclohexyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example232(b), using cyclohexyl isocyanate as the isocyanate of choice, and4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine ofchoice. MS(ES) m/e 352 [M+H]⁺.

Example 3034-Amino-3-(3-((butyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example232(b), using butyl isocyanate as the isocyanate of choice, and4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine ofchoice. MS(ES) m/e 326 [M+H]⁺.

Example 3044-Amino-3-(3-((tert-butyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example232(b), using t-butyl isocyanate as the isocyanate of choice, and4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine ofchoice. MS(ES) m/e 326 [M+H]⁺.

Example 3054-Amino-3-(3-(aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example232(b), using chlorosulfonyl isocyanate as the isocyanate of choice, and4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine ofchoice. MS(ES) m/e 270 [M+H]⁺.

Example 3064-Amino-3-(3-((5-indanyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example232(b), using 5-indanyl isocyanate as the isocyanate of choice, and4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine ofchoice. MS(ES) m/e 386 [M+H]⁺.

Example 3074-Amino-3-(3-((5-tert-butylisoxazol-3-yl)aminocarbonylamino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example232(b), using (5-t-butyl-isoxazol-3-yl)-carbamic acid phenyl ester asthe isocyanate of choice, and4-Amino-3-(3-aminophenyl)furo[2,3-d]pyrimidine (10) as the diamine ofchoice. MS(ES) m/e 393 [M+H]⁺.

Example 3084-Amino-3-(4-((3-cyanophenyl)aminocarbonylamino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example232(b), using 3-cyano-phenyl isocyanate as the isocyanate of choice.MS(ES) m/e 371 [M+H]⁺.

Example 3094-Amino-3-(4-((3-acetylphenyl)aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example232(b), using 3-acetyl-phenyl isocyanate as the isocyanate of choice.MS(ES) m/e 388 [M+H]⁺.

Example 3104-Amino-3-(4-((3-(methoxycarbonyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example232(b), using 3-isocyanato-benzoic acid methyl ester as the isocyanateof choice. MS(ES) m/e 404 [M+H]⁺.

Example 3114-Amino-3-(4-((3-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example232(b), using 3-fluoro-5-trifluromethyl-phenyl isocyanate as theisocyanate of choice. MS(ES) m/e 432 [M+H]⁺.

Example 3124-Amino-3-(4-((3-fluorophenyl)aminocarbonylamino)phenyl)-furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example232(b), using 3-fluoro-phenyl isocyanate as the isocyanate of choice.MS(ES) m/e 364 [M+H]⁺.

Example 3134-Amino-3-(4-((3-methoxyphenyl)aminocarbonylamino)phenyl)-furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example232(b), using 3-methoxy-phenyl isocyanate as the isocyanate of choice.MS(ES) m/e 376 [M+H]⁺.

Example 3144-Amino-3-(4-((3-methoxyphenylacetyl)amino)phenyl)furo[2,3-d]pyrimidine

The carboxylic acid of choice (3-methoxyphenyl acetic acid, 0.055 mmol)and 0.055 mmol of HBTU were dissolved in 0.5 mL amine-free DMF. To thissolution was added dropwise a solution of4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) in 0.5 mL DMF. Theresulting solution was treated with 0.024 mL ofN,N-diisopropylethylamine. The system was stirred at room temperatureovernight and then was concentrated to dryness in a Speedvac system,reconstituted in 1 mL DMSO and purified by prep HPLC to give the titlecompound. MS(ES) m/e 375 [M+H]⁺.

Example 3154-Amino-3-(4-((2-thienylacetyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described Example 314,using 2-thienylacetic acid as the carboxylic acid of choice. MS(ES) m/e351 [M+H]⁺.

Example 3164-Amino-3-(4-(((5-methyl-2-phenyloxazol-4-yl)acetyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example314, using 5-methyl-2-phenyloxazol-4-ylacetic acid as the carboxylicacid of choice. MS(ES) m/e 426 [M+H]⁺.

Example 3174-Amino-3-(4-(((3,5-bis-(trifluoromethyl)phenyl)acetyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example314, using 3,5-bis(trifluoromethyl)phenylacetic acid as the carboxylicacid of choice. MS(ES) m/e 481 [M+H]⁺.

Example 3184-Amino-3-(4-((benzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

To compound 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) (24 mg,0.044 mmol) in THF (1 mL), benzenesulfonyl chloride (6.8 uL, 0.053mmol), and N,N-diisopropylethylamine (9 uL, 0.053 mmol) were added.After the mixture was stirred at room temperature for 6 h, water wasadded to quench the reaction. The solution was extracted with EtOAc. Theorganic layer was separated, dried (MgSO4), and filtered. The solventwas evaporated. The residue was purified by gilson to afford the desiredproduct MS(ES) m/e 367 [M+H]⁺.

Example 3194-Amino-3-(4-((2,3-dichlorobenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2,3-dichloro-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 435 [M+H]⁺.

Example 3204-Amino-3-(4-((2,5-dichlorobenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2,5-dichloro-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 435 [M+H]⁺.

Example 3214-Amino-3-(4-(((5-chlorothiophene-2-sulfonyl)acetyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 5-chlorothiophene-2-sulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 407 [M+H]⁺.

Example 3224-Amino-3-(4-(((2,5-dichlorothiophene-3-sulfonyl)acetyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2,5-dichlorothiophene-3-sulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 441 [M+H]⁺.

Example 3234-Amino-3-(4-((3-fluorobenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 3-fluorobenzenesulfonyl chloride as the sulfonyl chloride ofchoice. MS(ES) m/e 385 [M+H]⁺.

Example 3244-Amino-3-(4-((3,4-dichlorobenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 3,4-dichlorobenzenesulfonyl chloride as the sulfonyl chlorideof choice. MS(ES) m/e 436 [M+H]⁺.

Example 3254-Amino-3-(4-((3-methoxybenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 3-methoxy-benzenesulfonyl chloride as the sulfonyl chlorideof choice. MS(ES) m/e 397 [M+H]⁺. Example 326

4-Amino-3-(4-((7-chloro-benzo[1,2,5]oxadiazole-4-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 7-chloro-benzo(1,2,5)oxadiazole-4-sulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 443 [M+H]⁺.

Example 3274-Amino-3-(4-((4-methoxybenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-methoxy-benzenesulfonyl chloride as the sulfonyl chlorideof choice. MS(ES) m/e 397 [M+H]⁺.

Example 328 4-Amino-3-(4-((5-chloro-1,3-dimethylpyrazole-4-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 5-chloro-1,3-dimethyl-1-pyrazole-4-sulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 419 [M+H]⁺.

Example 3294-Amino-3-(4-((4,5-dichlorothiophene-2-sulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4,5-dichloro-thiophene-2-sulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 441 [M+H]⁺.

Example 3304-Amino-3-(4-((2-phenylethenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using (E)-2-Phenyl-ethenesulfonyl chloride as the sulfonyl chlorideof choice. MS(ES) m/e 392 [M+H]⁺.

Example 3314-Amino-3-(4-((3,5-dichlorophenylsulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 3,5-dichloro-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 435 [M+H]⁺.

Example 3324-Amino-3-(4-((2-(methoxycarbonyl)thiophene-3-sulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester asthe sulfonyl chloride of choice. MS(ES) m/e 429 [M+H]⁺.

Example 3334-Amino-3-(4-((3-chlorobenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 3-chloro-benzenesulfonyl chloride as the sulfonyl chloride ofchoice. MS(ES) m/e 401 [M+H]⁺.

Example 3344-Amino-3-(4-((1-methyl-1H-imidazole-4-sulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 1-methyl-1H-imidazole-4-sulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 370 [M+H]⁺.

Example 3354-Amino-3-(4-((5-chlorobenzo[1,2,5]oxadiazole-4-sulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 5-chloro-benzo(1,2,5)oxadiazole-4-sulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 443 [M+H]⁺.

Example 3364-Amino-3-(4-((3,5-dimethoxybenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 3,5-dimethoxy-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 427 [M+H]⁺.

Example 3374-Amino-3-(4-((2,5-dimethoxybenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2,5-dimethoxy-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 427 [M+H]⁺.

Example 3384-Amino-3-(4-((2-chloro-4-fluorobenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2-chloro-4-fluoro-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 419 [M+H]⁺.

Example 3394-Amino-3-(4-((2-chloro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2-chloro-5-trifluoromethyl-benzenesulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 470 [M+H]⁺.

Example 3404-Amino-3-(4-((4-(methoxycarbonyl)-3-methoxythiophene-2-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 3-chlorosulfonyl-thiophene-2-carboxylic acid methyl ester asthe the sulfonyl chloride of choice. MS(ES) m/e 461 [M+H]⁺.

Example 3414-Amino-3-(4-((5-(1-methyl-5-(trifluoromethyl)pyrazol-3-yl)thiophene-2-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, 5-(methyl-trifluromethyl-1H-pyrazol-3-yl)-thiophene-2-sulfonylchloride as the sulfonyl chloride of choice. MS(ES) m/e 521 [M+H]⁺.

Example 3424-Amino-3-(4-((5-bromo-6-chloropyridine-3-sulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, 5-bromo-6-chloro-pyridine-3-sulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 481 [M+H]⁺.

Example 3434-Amino-3-(4-((2,3,4,5,6-pentafluorobenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2,3,4,5,6-pentafluoro-benzenesulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 457 [M+H]⁺.

Example 3444-Amino-3-(4-((4-(trifluoromethoxy)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-trifluoromethoxy-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 451 [M+H]⁺.

Example 3454-Amino-3-(4-((thiophene-2-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, thiophene-2-sulfonyl chloride as the sulfonyl chloride of choice.MS(ES) m/e 373 [M+H]⁺.

Example 3464-Amino-3-(4-((4-isopropylbenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-isopropyl-benzenesulfonyl chloride as the sulfonyl chlorideof choice. MS(ES) m/e 409 [M+H]⁺.

Example 3474-Amino-3-(4-((quinoline-8-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, quinoline-8-sulfonyl chloride as the sulfonyl chloride of choice.MS(ES) m/e 417 [M+H]⁺.

Example 3484-Amino-3-(4-((2-nitro-4-(trifluoromethyl)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2-nitro-4-trifluoromethyl-benzenesulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 480 [M+H]⁺.

Example 3494-Amino-3-(4-((2,4,6-trimethylbenzenesulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in makingExample 318, using 2,4,6-trimethyl-benzenesulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 408 [M+H]⁺.

Example 3504-Amino-3-(4-((5-bromo-2-methoxybenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 5-bromo-2-methoxy-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 476 [M+H]⁺.

Example 3514-Amino-3-(4-((4-propylbenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-propyl-benzenesulfonyl chloride as the sulfonyl chloride ofchoice. MS(ES) m/e 409 [M+H]⁺.

Example 3524-Amino-3-(4-((4-bromo-2,5-difluorobenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-bromo-2,5-difluoro-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 482 [M+H]⁺.

Example 3534-Amino-3-(4-((2,6-dichloro-4-(trifluoromethyl)benzenesulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2,6-dichloro-4-trifluoromethyl-benzenesulfonyl chloride asthe sulfonyl chloride of choice. MS(ES) m/e 504 [M+H]⁺.

Example 3544-Amino-3-(4-((2-(trifluoromethoxy)benzenesulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2-trifluoromethoxy-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 451 [M+H]⁺.

Example 3554-Amino-3-(4-((3,5-dimethylisoxazole-4-sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 3,5-Dimethyl-isoxazole-4-sulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 386 [M+H]⁺.

Example 3564-Amino-3-(4-((4-acetylbenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-acetyl-benzenesulfonyl chloride as the sulfonyl chloride ofchoice. MS(ES) m/e 408 [M+H]⁺.

Example 3574-Amino-3-(4-((2,4-dichlorobenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2,4-dichloro-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 435 [M+H]⁺.

Example 3584-Amino-3-(4-((3,5-bis-(trifluoromethyl)benzenesulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 3,5-bis-trifluoromethyl-benzenesulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 503 [M+H]⁺.

Example 3594-Amino-3-(4-((5-(N-(benzoyl)aminomethyl)thiophene-2-sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 5-(N-(benzoyl)aminomethyl)thiophene-2-sulfonyl chloride asthe the sulfonyl chloride of choice. MS(ES) m/e 506 [M+H]⁺.

Example 3604-Amino-3-(4-((2-(acetylamino)-4-methylthiazole-5-sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2-acetylamino-4-metyl-thiazole-5-sulfonyl chloride as the thesulfonyl chloride of choice. MS(ES) m/e 445 [M+H]⁺.

Example 3614-Amino-3-(4-((3-chloro-4-fluorobenzenesulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 3-chloro-4-fluoro-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 420 [M+H]⁺.

Example 362 4-Amino-3-(4-((4-ethylbenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-ethyl-benzenesulfonyl chloride as the sulfonyl chloride ofchoice. MS(ES) m/e 395 [M+H]⁺.

Example 3634-Amino-3-(4-((3,5-bis-(trifluoromethyl)phenylmethyl)sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using (3,5-bis-trifluoromethyl-phenyl)-methanesulfonyl chloride asthe sulfonyl chloride of choice. MS(ES) m/e 517 [M+H]⁺.

Example 3644-Amino-3-(4-((4-tert-butylbenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-tert-butyl-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 423 [M+H]⁺.

Example 3654-Amino-3-(4-((2-nitrophenylmethyl)sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using (2-nitro-phenyl)-methanesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 426 [M+H]⁺.

Example 3664-Amino-3-(4-((5-(isoxazol-3-yl)thiophene-2-sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 5-isoxazol-3-yl-thiophene-2-sulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 440 [M+H]⁺.

Example 3674-Amino-3-(4-((benzo[1,2,5]thiadiazole-4-sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using benzo(1,2,5)thiadiazole-4-sulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 425 [M+H]⁺.

Example 3684-Amino-3-(4-((4-cyanobenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-cyano-benzenesulfonyl chloride as the sulfonyl chloride ofchoice. MS(ES) m/e 392 [M+H]⁺.

Example 3694-Amino-3-(4-((benzo[1,4]dioxan-6-sulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2,3-dihydro-benzo(1,4)dioxine-6-sulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 425 [M+H]⁺.

Example 3704-Amino-3-(4-((5-(2-pyridyl)thiophene-2-sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 5-pyridin-2-yl-thiophene-2-sulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 450 [M+H]⁺.

Example 3714-Amino-3-(4-((3-(trifluoromethyl)phenylmethyl)sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using (3-trifluoromethyl-phenyl)-methanesulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 449 [M+H]⁺.

Example 3724-Amino-3-(4-((3,5-dichlorophenylmethyl)sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using (3,5-dichloro-phenyl)-methanesulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 450 [M+H]⁺.

Example 3734-Amino-3-(4-((5-(N-(4-chlorobenzoyl)aminomethyl)thiophene-2-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 5-(N-(4-chlorobenzoyl)aminomethyl)-thiophene-2-sulfonylchloride as the the sulfonyl chloride of choice. MS(ES) m/e 541 [M+H]⁺.

Example 3744-Amino-3-(4-((2,6-dichlorobenzenesulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2,6-dichloro-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 436 [M+H]⁺.

Example 3754-Amino-3-(4-((4-(benzenesulfonyl)thiophene-2-sulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-benzenesulfonyl-thiophene-2-sulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 513 [M+H]⁺.

Example 3764-Amino-3-(4-((4-bromo-2-ethylbenzenesulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-bromo-2-ethyl-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 474 [M+H]⁺.

Example 3774-Amino-3-(4-((3-chloro-2-methylbenzenesulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 3-chloro-2-methyl-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 416 [M+H]⁺.

Example 3784-Amino-3-(4-((5-bromothiophene-2-sulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 5-bromo-thiophene-2-sulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 452 [M+H]⁺.

Example 3794-Amino-3-(4-((4-fluorobenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-fluoro-benzenesulfonyl chloride as the sulfonyl chloride ofchoice. MS(ES) m/e 385 [M+H]⁺.

Example 3804-Amino-3-(4-((2-chlorobenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2-chloro-benzenesulfonyl chloride as the sulfonyl chloride ofchoice. MS(ES) m/e 402 [M+H]⁺.

Example 3814-Amino-3-(4-((5-(2-methylthio-pyrimidin-4-yl)thiophene-2-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 5-(2-methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonylchloride as the sulfonyl chloride of choice. MS(ES) m/e 497 [M+H]⁺.

Example 3824-Amino-3-(4-((5-(5-(trifluoromethyl)pyridine-2-sulfonyl)thiophene-2-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using5-(5-trifluoromethyl-pyridine-2-sulfonyl)-thiophene-2-sulfonyl chlorideas the sulfonyl chloride of choice. MS(ES) m/e 582 [M+H]⁺.

Example 3834-Amino-3-(4-((benzo[1,2,5]oxadiazole-4-sulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using benzo(1,2,5)oxadiazole-4-sulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 409 [M+H]⁺.

Example 3844-Amino-3-(4-((6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 6-chloro-imidazo(2,1b)thiazole-5-sulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 448 [M+H]⁺.

Example 3854-Amino-3-(4-((2,5-dimethylbenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2,5-dimethyl-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 395 [M+H]⁺.

Example 3864-Amino-3-(4-((5-(2-methylthiazol-4-yl)thiophene-2-sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 5-(2-methyl-thiazol-4-yl)-thiophene-2-sulfonyl chloride asthe sulfonyl chloride of choice. MS(ES) m/e 470 [M+H]⁺.

Example 3874-Amino-3-(4-((5-(5-trifluoromethyl-isoxazol-3-yl)thiophene-2-sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 5-(5-trifluoromethyl-isoxazole-3-yl)-thiophene-2-sulfonylchloride as the sulfonyl chloride of choice. MS(ES) m/e 508 [M+H]⁺.

Example 3884-Amino-3-(4-((2-methoxy-5-methylbenzenesulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2-methoxy-5-methyl-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 411 [M+H]⁺.

Example 3894-Amino-3-(4-((5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 5-chloro-3-methyl-benzo(b)-thiophene-2-sulfonyl chloride asthe sulfonyl chloride of choice. MS(ES) m/e 472 [M+H]⁺.

Example 3904-Amino-3-(4-((2,4-dichloro-5-methylbenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2,4-dichloro-5-methyl-benzenesulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 450 [M+H]⁺.

Example 3914-Amino-3-(4-((5-fluoro-2-methylbenzenesulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2-methyl-5-fluoro-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 399 [M+H]⁺.

Example 3924-Amino-3-(4-((5-chloronaphthalenesulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 5-chloro-naphthalene-1-sulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 452 [M+H]⁺.

Example 3934-Amino-3-(4-((4-(3,5-dichlorophenoxy)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-(3,5-dichloro-phenoxy)-benzenesulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 528 [M+H]⁺.

Example 3944-Amino-3-(4-((3-(4-chlorophenoxy)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 3-(4-chloro-phenoxy)-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 494 [M+H]⁺.

Example 3954-Amino-3-(4-(((4-pyridylmethyl)sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using pyridin-4-yl-methanesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 382 [M+H]⁺.

Example 3964-Amino-3-(4-((4-(2-pyridyloxy)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-(pyridin-2-yloxy)-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 461 [M+H]⁺.

Example 3974-Amino-3-(4-((5-([1,2,3]thiadiazol-4-yl)thiophene-2-sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, 5-(1,2,3)thiadiazol-4-yl-thiophene-2-sulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 457 [M+H]⁺.

Example 3984-Amino-3-(4-((5-(4-cyano-1-methyl-5-methylthio-1H-pyrazol-3-yl)thiophene-2-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, 5-(4-cyano-1-methyl-5-methylsulfanyl-1H-pyrazol-3-yl)-thiophene-2-sulfonyl chloride as the sulfonyl chlorideof choice. MS(ES) m/e 524 [M+H]⁺.

Example 3994-Amino-3-(4-((3-(4-chlorophenyl)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, 4-chloro-biphenyl-3-sulfonyl chloride as the sulfonyl chloride ofchoice. MS(ES) m/e 478 [M+H]⁺.

Example 4004-Amino-3-(4-((4-(4-pyridyloxy)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-(pyridin-4-yloxy)-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 461 [M+H]⁺.

Example 4014-Amino-3-(4-((4-butoxybenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-butoxy-benzenesulfonyl chloride as the sulfonyl chloride ofchoice. MS(ES) m/e 439 [M+H]⁺.

Example 4024-Amino-3-(4-((4-acetamide-3-chlorobenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-acetylamino-3-chloro-benzenesulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 459 [M+H]⁺.

Example 4034-Amino-3-(4-((4-(trifluoromethyl)phenylmethyl)sulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using (4-trifluoromethyl-phenyl)-methanesulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 449 [M+H]⁺.

Example 4044-Amino-3-(4-((4-chlorophenylmethyl)sulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using (4-chloro-phenyl)-methanesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 416 [M+H]⁺.

Example 4054-Amino-3-(4-((3,4-dichlorophenylmethyl)sulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using (3,4-dichloro-phenyl)-methanesulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 450 [M+H]⁺.

Example 4064-Amino-3-(4-((4-fluorophenylmethyl)sulfonyl)amino)phenyl)-furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using (4-fluoro-phenyl)-methanesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 399 [M+H]⁺.

Example 4074-Amino-3-(4-((6-(dimethylamino)naphthalene-1-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 6-dimethylamino-naphthalene-1-sulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 460 [M+H]⁺.

Example 4084-Amino-3-(4-((isoquinoline-5-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using isoquinoline-5-sulfonyl chloride as the sulfonyl chloride ofchoice. MS(ES) m/e 418 [M+H]⁺.

Example 4094-Amino-3-(4-((1-naphthalenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using naphthalene-1-sulfonyl chloride as the sulfonyl chloride ofchoice. MS(ES) m/e 417 [M+H]⁺.

Example 4104-Amino-3-(4-((phenylmethyl)sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using phenyl-methanesulfonyl chloride as the sulfonyl chloride ofchoice. MS(ES) m/e 381 [M+H]⁺.

Example 4114-Amino-3-(4-(((2-fluoro-5-(trifluoromethyl)phenylmethyl)-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using (2-fluoro-5-trifluoromethyl-phenyl)-methanesulfonyl chlorideas the sulfonyl chloride of choice. MS(ES) m/e 467 [M+H]⁺.

Example 4124-Amino-3-(4-((4-(3,4-dichlorophenoxy)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using (3,4-dichloro-phenoxy)-benzenesulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 528 [M+H]⁺.

Example 4134-Amino-3-(4-((4-(2-chlorothiazol-5-ylmethoxy)benzenesulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using (2-chloro-thiazol-5-ylmethoxy)-benzenesulfonyl chloride asthe sulfonyl chloride of choice. MS(ES) m/e 515 [M+H]⁺.

Example 4144-Amino-3-(4-((4-(3,4-dichlorophenyl)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 3′,4′-dichloro-biphenyl-4-sulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 512 [M+H]⁺.

Example 4154-Amino-3-(4-((4-(trifluoromethyl)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using trifluoromethyl-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 435 [M+H]⁺.

Example 4164-Amino-3-(4-((1,1-dioxo-tetrahydro-1/-thiophene-3-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 1,1-dioxo-tetrahydro-1/-thiophene-3-sulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 409 [M+H]⁺.

Example 4174-Amino-3-(4-((4-(phenylazo)benzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-phenylazo-benzenesulfonyl chloride as the sulfonyl chlorideof choice. MS(ES) m/e 471 [M+H]⁺.

Example 4184-Amino-3-(4-((2,5-dibromo-3,6-difluorobenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2,5-dibromo-3,6-difluoro-benzenesulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 561 [M+H]⁺.

Example 4194-Amino-3-(4-((4-bromo-2-(trifluoromethoxy)benzenesulfonyl)-amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 530 [M+H]⁺.

Example 4204-Amino-3-(4-((2-chloro-4-cyanobenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2-chloro-4-cyano-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 427 [M+H]⁺.

Example 4214-Amino-3-(4-((2,3,5,6-tetramethylbenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 2,3,5,6-tetramethyl-benzenesulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 423 [M+H]⁺.

Example 4224-Amino-3-(4-((3,5-dichloro-2-hydroxybenzenesulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 3,5-dichloro-2-hydroxy)-benzenesulfonyl chloride as thesulfonyl chloride of choice. MS(ES) m/e 452 [M+H]⁺.

Example 4234-Amino-3-(4-((3-chloro-4-(1,3-dioxo-2-aza-spiro(4,4)non-2-yl)benzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using3-chloro-4-[1,3-dioxo-2-aza-spiro(4,4)non-2-yl]-benzenesulfonyl chlorideas the sulfonyl chloride of choice. MS(ES) m/e 553 [M+H]⁺.

Example 4244-Amino-3-(4-(((2-chloro-5-(trifluoromethyl)phenylmethyl)-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using (2-chloro-5-trifluoromethyl-phenyl)-methanesulfonyl chlorideas the sulfonyl chloride of choice. MS(ES) m/e 483 [M+H]⁺.

Example 4254-Amino-3-(4-(((p-tolylmethyl)sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using p-tolyl-methanesulfonyl chloride as the sulfonyl chloride ofchoice. MS(ES) m/e 395 [M+H]⁺.

Example 4264-Amino-3-(4-(((1,2-dimethyl-1H-imidazol-4-yl)sulfonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride as the sulfonylchloride of choice. MS(ES) m/e 385 [M+H]⁺.

Example 4274-Amino-3-(4-((5-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)thiophene-2-sulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using5-(chloro-trifluoromethyl-pyridin-2-ylmethyl)-thiophene-2-sulfonylchloride as the sulfonyl chloride of choice. MS(ES) m/e 567 [M+H]⁺.

Example 4284-Amino-3-(4-((4-butylbenzenesulfonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example318, using 4-butyl-benzenesulfonyl chloride as the sulfonyl chloride ofchoice. MS(ES) m/e 423 [M+H]⁺.

Preparation of Intermediates 10–13 following are depicted in Scheme 10.

Intermediate Example 10 2-[1-(4-Nitrophenyl)-ethylidene]-malononitrile

p-Nitro-acetophenone (165 g/mole; 4.0 g; 24 mmoles), ammonium acetate(0.50 g) and glacial acetic acid (0.80 mL) were added to a round-bottomflask containing 20 mL toluene, and heated to reflux using a Dean-Starktrap and a reflux condenser. Separately, malononitrile (66 g/mole; 2.0g; 30.3 mmoles) was dissolved in 5 mL dioxane and 20 mL toluene,transferred to an addition funnel and added dropwise to the heatedsolution of ketone. Upon completion of the addition, the system washeated for 2 hours and then cooled to room temperature. The reactionmixture was poured into 150 mL brine and 100 mL ethyl acetate. Theaqueous layer was separated and washed with 50 mL ethyl acetate. Theorganic layers were combined and dried over anhydrous sodium sulfate.The solvent was removed in vacuo and the crude product2-[1-(4-nitrophenyl)-ethylidene]-malononitrile (213 g/mole) was used assuch in Intermediate Example 11.

Intermediate Example 112-Amino-4-(4-nitro-phenyl)-thiophene-3-carbonitrile

Crude 2-[1-(4-nitrophenyl)-ethylidene]-malononitrile (24 mmoles assumed)was treated with sulfur (2 g) and 50 mL DMF. The system was heated to120° C. in an oil bath. When the reaction was judged complete by TLC(product has Rf=0.44 in 40% ethyl acetate-hexane), the mixture wascooled to room temperature and poured into 50 mL brine and 100 mL ethylacetate. The yellow solid that separated (mostly sulfur) was removed byfiltration. The organic layer was washed with 3×50 mL brine, and thecombined aqueous layers were back-extracted with 50 mL ethyl acetate.The combined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated to dryness. The residue was treated with 100mL methylene chloride, warmed to reflux, cooled to 15° C. and filtered.The resulting yellow precipitate was mostly desired product2-amino-4-(4-nitro-phenyl)-thiophene-3-carbonitrile (245 g/mole; ˜50%yield from p-nitro-acetophenone; MP 193–195° C. (dec)).

Intermediate Example 12 4-Amino-3-(4-nitrophenyl)thieno[2,3-d]pyrimidine

2-Amino-4-(4-nitrophenyl)-thiophene-3-carbonitrile (17.5 g; 245 g/mole;71.5 moles) was heated in 250 mL formamide at 200° C. for 15 minutes andcooled to room temperature. The dark solution was poured into 1 Lmethylene chloride and 500 mL brine. A dark precipitate (A) formed andwas collected by filtration. The filtrate (B) was reserved. Precipitate(A) was washed with 3×500 mL hot ethyl acetate. The washings werereserved, while the solid constituted crude product (Rf=0.76 in 100%ethyl acetate). Filtrate (B) was decanted and the organic layer wasreserved. The aqueous layer was washed with 2×100 mL ethyl acetate, andthe resulting stripped aqueous layer was discarded. All organic layers,including washings, were combined and concentrated to dryness. Theresulting solid residue was submitted to washings with hot ethylacetate. The resulting washed solid was combined with the previous cropof crude product, in a total ˜36% yield of4-Amino-3-(4-nitrophenyl)-thieno[2,3-d]pyrimidine in 3 steps.

Intermediate Example 13 4-Amino-3-(4-aminophenyl)thieno[2,3-d]pyrimidine

4-Amino-3-(4-nitrophenyl)thieno[2,3-d]pyrimidine (11.6 g; 272 g/mole;42.6 mmoles) was treated with 500 mL HCl 6N and 15 g elemental tin atroom temperature. After 15 minutes the reaction was complete by TLC(product has Rf=0.50 in 100% ethyl acetate). The system was placed in anice bath and treated with concentrated ammonium hydroxide to pH 10 (˜300mL). At this point, extensive precipitation was observed. Precipitate(A) was collected by filtration and reserved, and the clear solution wastreated with 1 L methylene chloride. The aqueous layer was thenback-extracted with 3×200 mL methylene chloride. The organic layers werecombined, dried over anhydrous sodium sulfate, and filtered. Precipitate(A), consisting of a mixture of tin salts and product, was extractedwith boiling methanol until washings showed no more product by TLC. Theresulting solution was combined with the previously reserved organiclayers, filtered, concentrated to dryness and dried overnight,generating desired product4-Amino-3-(4-aminophenyl)thieno[2,3-d]pyrimidine (242 g/mole; nearlyquantitative yield), which was recrystallized from methanol.

Example 4294-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)thieno[2,3-d]pyrimidine

4-Amino-3-(4-aminophenyl)thieno[2,3-d]pyrimidine (0.2 mmoles) wasdissolved in 1 mL amine-free DMF and treated with 0.3 mmoles of theisocyanate of choice (2-fluoro-5-trifluoromethyl-phenyl isocyanate) and0.6 mmoles of diisopropylethylamine for 2 hours at room temperature. Thereaction mixture was treated with 0.5 mL 1:1 methanol-triethylamine forhalf an hour and concentrated to dryness in a Speedvac system,reconstituted in 1 mL DMSO and purified by prep HPLC. The fractioncontaining the desired product was collected and concentrated todryness. MH+=448.

Example 4304-Amino-3-(4-((5-indanyl)aminocarbonylamino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example429, using 3-indan-5-yl isocyanate as the isocyanate of choice. MH+=402.

Example 4314-Amino-3-(4-((2-methylphenyl)aminocarbonylamino)phenyl)-thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example429, using o-tolyl isocyanate as the isocyanate of choice. MH+=376.

Example 4324-Amino-3-(4-((3-methylphenyl)aminocarbonylamino)phenyl)-thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example429, using m-tolyl isocyanate as the isocyanate of choice. MH+=376.

Example 4334-Amino-3-(4-((3-(trifluoromethyl)phenyl)aminocarbonylamino)-phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example429, using m-trifluoromethylphenyl isocyanate as the isocyanate ofchoice. MH+=430.

Example 4344-Amino-3-(4-((2-chloro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example429, using 2-chloro-5-trifluoromethyl-phenyl isocyanate as theisocyanate of choice. MH+=464.

Example 4354-Amino-3-(4-(((2,5-difluorophenyl)acetyl)amino)phenyl)thieno[2,3-d]pyrimidine

0.25 mmoles of the carboxylic acid of choice (2,5-difluorophenyl-aceticacid; 0.25 mmoles) and 0.25 mmoles of HBTU were dissolved in 1 mLamine-free DMF. To this solution was added dropwise a solution of4-Amino-3-(4-aminophenyl)thieno[2,3-d]-pyrimidine in 1 mL DMF. Theresulting solution was treated with 0.3 mL of Hunig's base. The systemwas stirred at room temperature overnight and then treated with 0.5 mLof 1:1 MeOH-diethylamine. The system was concentrated to dryness in aSpeedvac system, reconstituted in 1 mL DMSO and purified by prep HPLC.MH+=397.

Example 4364-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)benzoyl)amino)-phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 2-fluoro-5-trifluoromethyl-benzoic acid as the carboxylicacid of choice. MH+=433.

Example 437 4-Amino-3-(4-(benzoylamino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using benzoic acid as the carboxylic acid of choice. MH+=347.

Example 4384-Amino-3-(4-((2,6-difluorobenzoyl)amino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 2,6-difluorobenzoic acid as the carboxylic acid of choice.MH+=383.

Example 4394-Amino-3-(4-(((S)-2-amino-2-phenylacetyl)amino)phenyl)-thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using (S)-N-Boc-2-amino-phenylacetic acid as the carboxylic acid ofchoice. After amide coupling and HPLC purification, the Boc-containingproduct was stirred with 20% trifluoroacetic acid-methylene chloride for5 minutes, concentrated to dryness and purified by HPLC to afford thedesired product MH+=376.

Example 4404-Amino-3-(4-(((1S,2S)-2-phenyl-cyclopropanecarbonyl)amino)-phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using (1S,2S)-2-phenyl-cyclopropanecarboxylic acid as thecarboxylic acid of choice. MH+=387.

Example 4414-Amino-3-(4-((2,5-difluorobenzoyl)amino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 2,5-difluorophenylacetic acid as the carboxylic acid ofchoice. MH+=383.

Example 4424-Amino-3-(4-(((R)-2-amino-2-phenylacetyl)amino)phenyl)-thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using (R)-N-Boc-2-amino-phenylacetic acid as the carboxylic acid ofchoice. After amide coupling and HPLC purification, the Boc-containingproduct was stirred with 20% trifluoroacetic acid-methylene chloride for5 minutes, concentrated to dryness and purified by HPLC to afford thedesired product MH+=376.

Example 4434-Amino-3-(4-((1-phenyl-cyclopropanecarbonyl)amino)-phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 1-phenyl-cyclopropanecarboxylic acid as the carboxylic acidof choice. MH+=387.

Example 4444-Amino-3-(4-(((2,6-difluorophenyl)acetyl)amino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 2,6-difluorophenylacetic acid as the carboxylic acid ofchoice. MH+=397.

Example 4454-Amino-3-(4-((phenylacetyl)amino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using phenylacetic acid as the carboxylic acid of choice. MH+=361.

Example 4464-Amino-3-(4-(((3,5-bis-(trifluoromethyl)phenyl)acetyl)amino)-phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 3,5-bis-trifluoromethyl-phenylacetic acid as the carboxylicacid of choice. MH+=497.

Example 4474-Amino-3-(4-(((2,4-bis-(trifluoromethyl)phenyl)acetyl)amino)-phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 2,4-bis-trifluoromethyl-phenylacetic acid as the carboxylicacid of choice. MH+=497.

Example 4484-Amino-3-(4-(((3-(trifluoromethylthio)phenyl)acetyl)amino)-phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 3-trifluoromethylthio-phenylacetic acid as the carboxylicacid of choice. MH+=461.

Example 4494-Amino-3-(4-(((1R,2R)-2-phenyl-cyclopropanecarbonyl)amino)-phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using (1R,2R)-2-phenyl-cyclopropanecarboxylic acid as thecarboxylic acid of choice. MH+=387.

Example 4504-Amino-3-(4-(((E)-3-(2-chlorophenyl)acryloyl)amino)-phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using (E)-3-(2-chlorophenyl)-acrylic acid as the carboxylic acid ofchoice. MH+=407.

Example 4514-Amino-3-(4-(((E)-3-(3-chlorophenyl)acryloyl)amino)-phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using (E)-3-(3-chlorophenyl)-acrylic acid as the carboxylic acid ofchoice. MH+=407.

Example 4524-Amino-3-(4-(((E)-3-phenylacryloyl)amino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using (E)-3-phenyl-acrylic acid as the carboxylic acid of choice.MH+=373.

Example 4534-Amino-3-(4-((1-phenylcyclopentanecarbonyl)amino)-phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using phenylcyclopentanecarboxylic acid as the carboxylic acid ofchoice. MH+=415.

Example 4544-Amino-3-(4-((2-phenylisobutyryl)amino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 2-methyl-2-phenylpropionic acid as the carboxylic acid ofchoice. MH+=389.

Example 4554-Amino-3-(4-(((2-fluoro-5-(trifluoromethyl)phenyl)acetyl)amino)-phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 2-fluoro-5-trifluoromethyl-phenyl)-acetic acid as thecarboxylic acid of choice. MH+=447.

Example 4564-Amino-3-(4-(((2,5-dichlorothiophene-3-yl)carbonyl)amino)-phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 2,5-dichloro-thiophene-3-carboxylic acid as the carboxylicacid of choice. MH+=422.

Example 4574-Amino-3-(4-(((bicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)carbonyl)-amino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using bicyclo[4.2.0]octa-1(6),2,4-triene-7-carboxylic acid as thecarboxylic acid of choice. MH+=373.

Example 4584-Amino-3-(4-((2-phenylbutyryl)amino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 2-phenyl-butyric acid as the carboxylic acid of choice.MH+=389.

Example 4594-Amino-3-(4-(((5-methyl-[1,3,4]thiadiazol-2-yl)carbonyl)amino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 5-methyl-[1,3,4]thiadiazole-2-carboxylic acid as thecarboxylic acid of choice. MH+=369.

Example 4604-Amino-3-(4-(((5-tert-butyl-2-methyl-2H-pyrazol-3-yl)carbonyl)amino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid as thecarboxylic acid of choice. MH+=407.

Example 4614-Amino-3-(4-((4-(4-methyl-piperazin-1-yl-methyl)benzoyl)amino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid as thecarboxylic acid of choice. MH+=459.

Example 4624-Amino-3-(4-((3-cyanobenzoyl)amino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 3-cyano-benzoic acid as the carboxylic acid of choice.MH+=372.

Example 4634-Amino-3-(4-((2-methoxybenzoyl)amino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 2-methoxy-benzoic acid as the carboxylic acid of choice.MH+=377.

Example 4644-Amino-3-(4-((3-chlorobenzoyl)amino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 3-chloro-benzoic acid as the carboxylic acid of choice.MH+=381

Example 4654-Amino-3-(4-((3-methoxybenzoyl)amino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 3-methoxy-benzoic acid as the carboxylic acid of choice.MH+=377.

Example 4664-Amino-3-(4-((4-(trifluoromethoxy)benzoyl)amino)phenyl)-thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example435, using 4-trifluoromethoxy-benzoic acid as the carboxylic acid ofchoice. MH+=431.

Example 4674-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonyl(N-methylamino))phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example429, substituting4-amino-3-(4-(methylamino)phenyl)-thieno[2,3-d]pyrimidine as the amineand using 2-fluoro-5-trifluoromethyl-phenyl isocyanate as the isocyanateof choice. MH+=462.

Example 4684-Amino-3-(4-((3-ethylphenyl)aminocarbonyl(N-methylamino))-phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example429, substituting4-amino-3-(4-(methylamino)phenyl)-thieno[2,3-d]pyrimidine as the amineand using 2-ethyl-phenyl isocyanate as the isocyanate of choice.MH+=404.

Schemes 11–13 depict the preparation of Examples 469–479.

Example 4694-Amino-3-(4-((1-(3,4-dichlorophenyl)-cyclopropanecarbonyl)amino)phenyl)thieno[2,3-d]pyrimidine

a) 1-(3,4-Dichloro-phenyl)-cyclopropanecarbonitrile

To a stirred mixture of 3,4-Dichloro-phenylacetonitrile (4.65 g. 25mmol) triethylbenzylammonium chloride (0.2 g) and 1-bromochoroethane(4.2 ml, 50 mmol), 50% sodium hydroxide (16 ml, 200 mmol) was addeddropwise at 50° then the reaction was stirred at 50° for 10 hrs. Aftercooling to rt, the reaction mixture was diluted with water and extractedwith EtOAc (×3). The layers were separated, washed with water (×3) andbrine, then dried over MgSO₄. Evaporation of the solvent under reducedpressure afforded the title compound (5.43 g) which was thenrecrystallized from Et₂O/hexanes as a pale pink solid (4.49 g, 85%).Lc/MS(ES) m/e 212 [M+H]⁺.

b) 1-(3,4-Dichloro-phenyl)-cyclopropanecarboxylic acid

1-(3,4-Dichloro-phenyl)-cyclopropanecarbonitrile (2 g, 9.48 mmol) washeated at 100° overnight in a sealed vessel in cone. HCl (10 ml). Thereaction was poured into ice water and extracted with tBuOMe (×2),washed with water (×2) and brine, then dried over MgSO₄ and evaporatedunder reduced pressure to give the title compound which wasrecrystallized from Et₂O/hexane as a white solid. (2.26 g, quant.)Lc/MS(ES) m/e 231[M+H]⁺.

c) 1-(3,4-Dichloro-phenyl)-cyclopropanecarbonyl chloride

1-(3,4-Dichloro-phenyl)-cyclopropanecarboxylic acid (1 g, 4.35 mmol) wasstirred in thionyl chloride (2 ml) at 37° for 72 h then the thionylchloride was removed under reduced pressure. The residue was rotovappedfrom benzene (×3) affording the title compound as a yellow oil. (1.1 g,quant) ¹H NMR(400 MHz, CDCl3) δ 7.46 (dd, J=8.3 Hz, 4.4 Hz, 2H), 7.23(d, J=8.3, 1H), 2.00 (dd, J=4.6, Hz, 7.6 Hz, 2H), 1.485(dd, J=4.6, Hz,7.6 Hz, 2H).

d)4-Amino-3-(4-((1-(3,4-dichlorophenyl)-cyclopropanecarbonyl)amino)phenyl)thieno[2,3-d]pyrimidine

To a solution of 4-Amino-3-(4-aminophenyl)thieno[2,3-d]pyrimidine (0.3mL of a 0.324 M solution, 0.1 mmol)1-(3,4-Dichloro-phenyl)-cyclopropanecarbonyl chloride (0.2 mL of a 1 Msolution in pyridine, 0.2 mmol) was added in one portion. After themixture was stirred at room temperature for 3 d, the reaction waspurified by hplc to afford the title compound as a beige solid. MS(ES)m/e 455 [M+H].

Example 4704-Amino-3-(4-((1-(2,5-difluorophenyl)-cyclopropanecarbonyl)amino)phenyl)thieno[2,3-d]pyrimidine

a) 1-(2,5-Difluoro-phenyl)-cyclopropanecarbonyl chloride

Utilizing the procedure of Example 469(a)–(c), except substituting2,5-Difluoro-phenylacetonitrile for 3,4-Dichloro-phenylacetonitrile, thetitle compound was prepared (1.17, 92%). ¹H NMR(400 MHz, CDCl3) δ7.13–6.98 (m, 3H), 2.03(dd, J=4.6, Hz, 7.8 Hz, 2H), 1.50(dd, J=4.6, Hz,7.8 Hz, 2H).

b)4-Amino-3-(4-((1-(2,5-difluorophenyl)-cyclopropanecarbonyl)amino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example469, using 1-(2,5-Difluoro-phenyl)-cyclopropanecarbonyl chloride as theacid chloride of choice, and4-Amino-3-(4-aminophenyl)thieno[2,3-d]pyrimidine as the diamine ofchoice. MS(ES) m/e 423 [M+H]⁺.

Example 4714-Amino-3-(4-((1-(3,5-bis-(trifluoromethyl)phenyl)-cyclopropanecarbonyl)amino)phenyl)thieno[2,3-d]pyrimidine

a) 1-(Bis-3,5-trifluoromethyl-phenyl)-cyclopropanecarbonyl chloride

Following the procedure of Example 469(a)–(c), except substituting(Bis-3,5-trifluoromethyl-phenyl)-acetonitrile for3,4-Dichloro-phenylacetonitrile, the title compound was prepared (1.07,97¹H NMR(400 MHz, CDCl3) δ 7.88 (s, 1H), 7.84 (s, 2H), 2.11 (dd, J=4.6,Hz, 7.6 Hz, 2H), 1.58 (dd, J=4.8, Hz, 7.6 Hz, 2H).

b)4-Amino-3-(4-((1-(3,5-bis-(trifluoromethyl)phenyl)-cyclopropanecarbonyl)amino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example469, using 1-(Bis-3,5-trifluoromethyl-phenyl)-cyclopropanecarbonylchloride as the acid chloride of choice, and4-Amino-3-(4-aminophenyl)thieno[2,3-d]pyrimidine as the diamine ofchoice. MS(ES) m/e 523 [M+H]⁺.

Example 4724-Amino-3-(4-((1-(3-chlorophenyl)cyclopropanecarbonyl)amino)-phenyl)thieno[2,3-d]pyrimidine

a) 1-(3-chloro-phenyl)-cyclopropanecarbonyl chloride

Following the procedure of Example 469(b)–(c), except substituting1-(3-chloro-phenyl)-cyclopropanecarbonitrile for1-(3,4-Dichloro-phenyl)-cyclopropanecarbonitrile, the title compound wasprepared (0.230, 75%). Characterized by dissolving in MeOH, MS(ES) m/e210 [M+H]⁺(methyl ester).

b)4-Amino-3-(4-((1-(3-chlorophenyl)cyclopropanecarbonyl)-amino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example469, using 1-(3-chloro-phenyl)-cyclopropanecarbonyl chloride as the acidchloride of choice, and 4-Amino-3-(4-aminophenyl)thieno[2,3-d]pyrimidineas the diamine of choice. MS(ES) m/e 421 [M+H]⁺.

Example 4734-Amino-3-(4-((1-(3-(trifluoromethyl)phenyl)-cyclopropanecarbonyl)amino)phenyl)thieno[2,3-d]pyrimidine

a) 1-(3-Trifluoromethyl-phenyl)-cyclopropanecarbonyl chloride

Following the procedure of Example 469 (a)–(c), except substituting3-Trifluoromethyl-phenylacetonitrile for 3,4-Dichloro-phenylacetonitrilewith prolonged heating for the hydrolysis (8 days at 120°, the titlecompound was prepared. ¹H NMR(400 MHz, CDCl3) δ 7.63–749 (m, 4H), 2.05(dd, J=4.6, Hz, 7.6 Hz, 2H), 1.53 (dd, J=4.6, Hz, 7.6 Hz, 2H).

b)4-Amino-3-(4-((1-(3-(trifluoromethyl)phenyl)-cyclopropanecarbonyl)amino)phenyl)thieno[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example469, using 1-(3-Trifluoromethyl-phenyl)-cyclopropanecarbonyl chloride asthe acid chloride of choice, and4-Amino-3-(4-aminophenyl)thieno[2,3-d]pyrimidine as the diamine ofchoice. MS(ES) m/e 455 [M+H]⁺.

Example 4744-Amino-3-(4-((1-(3,4-dichlorophenyl)-cyclopropanecarbonyl)amino)phenyl)furo[2,3-d]pyrimidine

a) 1-(3,4-Dichloro-phenyl)-cyclopropanecarbonitrile

To a stirred mixture of 3,4-Dichloro-phenylacetonitrile (4.65 g. 25mmol) triethylbenzylammonium chloride (0.2 g) and 1-bromochoroethane(4.2 ml, 50 mmol), 50% sodium hydroxide (16 ml, 200 mmol) was addeddropwise at 50° then the reaction was stirred at 50° for 10 hrs. Aftercooling to rt, the reaction mixture was diluted with water and extractedwith EtOAc (×3). The layers were separated, washed with water (×3) andbrine, then dried over MgSO₄. Evaporation of the solvent under reducedpressure afforded the title compound (5.43 g) which was thenrecrystallized from Et₂O/hexanes as a pale pink solid (4.49 g, 85%).Lc/MS(ES) m/e 212 [M+H]⁺.

b) Preparation of 1-(3,4-Dichloro-phenyl)-cyclopropanecarboxylic acid

1-(3,4-Dichloro-phenyl)-cyclopropanecarbonitrile (2 g, 9.48 mmol) washeated at 100° overnight in a sealed vessel in cone. HCl (10 ml). Thereaction was poured into ice water and extracted with tBuOMe (×2),washed with water (×2) and brine, then dried over MgSO₄ and evaporatedunder reduced pressure to give the title compound which wasrecrystallized from Et₂O/hexane as a white solid. (2.26 g, quant.)Lc/MS(ES) m/e 231 [M+H]⁺.

c) Preparation of 1-(3,4-Dichloro-phenyl)-cyclopropanecarbonyl chloride

1-(3,4-Dichloro-phenyl)-cyclopropanecarboxylic acid (1 g, 4.35 mmol) wasstirred in thionyl chloride (2 ml) at 37° for 72 h then the thionylchloride was removed under reduced pressure the residue was rotovappedfrom benzene (×3) affording the title compound as a yellow oil. (1.1 g,quant) ¹H NMR(400 MHz, CDCl3) δ 7.46 (dd, J=8.3 Hz, 4.4 Hz, 2H), 7.23(d, J=8.3, 1H), 2.00 (dd, J=4.6, Hz, 7.6 Hz, 2H), 1.485(dd, J=4.6, Hz,7.6 Hz, 2H).

d)4-Amino-3-(4-((1-(3,4-dichlorophenyl)-cyclopropanecarbonyl)amino)phenyl)furo[2,3-d]pyrimidine

To compound 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) (0.3 mLof a 0.324 M solution in pyridine 0.1 mmol)1-(3,4-Dichloro-phenyl)-cyclopropanecarbonyl chloride (0.2 mL of a 1 Msolution in pyridine, 0.2 mmol) was added in one portion. After themixture was stirred at room temperature for 3 d, the reaction waspurified by hplc to afford the title compound. MS(ES) m/e 439 [M+H].

Example 4754-Amino-3-(4-((1-(2.5-difluorophenyl)-cyclopropanecarbonyl)amino)phenyl)furo[2,3-d]pyrimidine

a) 1-(2,5-Difluoro-phenyl)-cyclopropanecarbonyl chloride

Following the procedure of Example 474 (a)–(c), except substituting2,5-Difluoro-phenylacetonitrile for 3,4-Dichloro-phenylacetonitrile, thetitle compound was prepared (1.17, 92%). ¹H NMR(400 MHz, CDCl3)δ7.13–6.98 (m, 3H), 2.03(dd, J=4.6, Hz, 7.8 Hz, 2H), 1.50(dd, J=4.6, Hz,7.8 Hz, 2H).

b)4-Amino-3-(4-((1-(2,5-difluorophenyl)-cyclopropanecarbonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example474, using 1-(2,5-Difluoro-phenyl)-cyclopropanecarbonyl chloride as theacid chloride of choice, and4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) as the diamine ofchoice. MS(ES) m/e 407 [M+H]⁺.

Example 4764-Amino-3-(4-((1-(3,5-bis-(trifluoromethyl)phenyl)-cyclopropanecarbonyl)amino)phenyl)furo[2,3-d]pyrimidine

a) 1-(Bis-3,5-trifluoromethyl-phenyl)-cyclopropanecarbonyl chloride

Following the procedure of Example 474 (a)–(c), except substituting(Bis-3,5-trifluoromethyl-phenyl)-acetonitrile for3,4-Dichloro-phenylacetonitrile, the title compound was prepared (1.07,97¹H NMR(400 MHz, CDCl3) δ 7.88 (s, 1H), 7.84 (s, 2H), 2.11 (dd, J=4.6,Hz, 7.6 Hz, 2H), 1.58 (dd, J=4.8, Hz, 7.6 Hz, 2H).

b)4-Amino-3-(4-((1-(3,5-bis-(trifluoromethyl)phenyl)-cyclopropanecarbonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example474, using 1-(Bis-3,5-trifluoromethyl-phenyl)-cyclopropanecarbonylchloride as the acid chloride of choice, and4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) as the diamine ofchoice. MS(ES) m/e 507 [M+H]⁺.

Example 4774-Amino-3-(4-((1-(3-chlorophenyl)cyclopropanecarbonyl)amino)-phenyl)furo[2,3-d]pyrimidine

a) 1-(3-chloro-phenyl)-cyclopropanecarbonyl chloride

Following the procedure of Example 474 (b)–(c), except substituting1-(3-chloro-phenyl)-cyclopropanecarbonitrile for1-(3,4-Dichloro-phenyl)-cyclopropanecarbonitrile, the title compound wasprepared (0.230, 75%). Characterized by dissolving in MeOH, MS(ES) m/e210 [M+H]⁺(methyl ester).

b)4-Amino-3-(4-((1-(3-chlorophenyl)cyclopropanecarbonyl)-amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example474, using 1-(3-chloro-phenyl)-cyclopropanecarbonyl chloride as the acidchloride of choice, and 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine(9) as the diamine of choice. MS(ES) m/e 405 [M+H]⁺.

Example 4784-Amino-3-(4-((1-phenylcyclopropanecarbonyl)amino)-phenyl)furo[2,3-d]pyrimidine

a) 1-(Phenyl)-cyclopropanecarbonyl chloride

Following the procedure of Example 474 (c), except substituting1-(Phenyl)-cyclopropanecarboxylic acid for1-(3,4-Dichloro-phenyl)-cyclopropanecarboxylic acid, the title compoundwas prepared (3.0, quant.). ¹H NMR(400 MHz, CDCl3) 7.3 (m, 5H), 2.02(dd, 2H), 1.56 (dd, 2H).

b)4-Amino-3-(4-((1-phenylcyclopropanecarbonyl)amino)-phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in Example474, using 1-Phenyl-cyclopropanecarbonyl chloride as the acid chlorideof choice, and 4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) as thediamine of choice. MS(ES) m/e 371 [M+H]⁺.

Example 4794-Amino-3-(4-((1-(3-(trifluoromethyl)phenyl)-cyclopropanecarbonyl)amino)phenyl)furo[2,3-d]pyrimidine

a) 1-(3-Trifluoromethyl-phenyl)-cyclopropanecarbonyl chloride Followingthe procedure of Example 474 (a)–(c), except substituting3-Trifluoromethyl-phenylacetonitrile for 3,4-Dichloro-phenylacetonitrilewith prolonged heating for the hydrolysis (8 days at 120°, the titlecompound was prepared. ¹H NMR(400 MHz, CDCl3) δ 7.63–749 (m, 4H), 2.05(dd, J=4.6, Hz, 7.6 Hz, 2H), 1.53 (dd, J=4.6, Hz, 7.6 Hz, 2H).

b)4-Amino-3-(4-((1-(3-(trifluoromethyl)phenyl)-cyclopropanecarbonyl)amino)phenyl)furo[2,3-d]pyrimidine

The compound was prepared following the procedure described in makingExample 474, using 1-(3-Trifluoromethyl-phenyl)-cyclopropanecarbonylchloride as the acid chloride of choice, and4-Amino-3-(4-aminophenyl)furo[2,3-d]pyrimidine (9) as the diamine ofchoice. MS(ES) m/e 436 [M+H]⁺.

Biological Data

TIE-2 Enzyme assay (TIE2-E)

The TIE-2 enzyme assay used the LANCE method (Wallac) and GST-TIE2,baculovirus expressed recombinant constructs of the intracellulardomains of human TIE2 (amino acids 762-1104, GenBank Accession #L06139)tagged by GST). The method measured the ability of the purified enzymesto catalyse the transfer of the γ-phosphate from ATP onto tyrosineresidues in a biotinylated synthetic peptide, D1–15(biotin-C6-LEARLVAYEGWVAGKKKamide). This peptide phosphorylation wasdetected using the following procedure: for enzyme preactivation,GST-TIE2 was incubated for 30 mins at room temperature with 2 mM ATP, 5mM MgCl2 and 12.5 mM DTT in 22.5 mM HEPES buffer (pH 7.4). PreactivatedGST-TIE2 was incubated for 30 mins at room temperature in 96 well plateswith 1 uM D1–15 peptide, 80 uM ATP, 10 mM MgCl2, 0.1 mg/ml BSA and thetest compound (diluted from a 10 mM stock in DMSO, final DMSOconcentration was 2.4%) in 1 mM HEPES (pH 7.4). The reaction was stoppedby the addition of EDTA (final concentration 45 mM). Streptavidinlinked-APC (allophycocyanin, Molecular Probe) and Europium-labeledanti-phosphorylated tyrosine antibody (Wallac) were then added at thefinal concentration of 17 ug/well and 2.1 ug/well, respectively. The APCsignal was measured using an ARVO multilabel counter. (Wallac BertholdJapan). The percent inhibition of activity was calculated relative toblank control wells. The concentration of test compound that inhibits50% of activity (IC₅₀) was interpolated using nonlinear regression(Levernberg-Marquardt) and the equation, y=Vmax (1−x/(K+x))+Y2, where“K” was equal to the IC₅₀. The IC₅₀ values were converted to pIC₅₀values, i.e., −log IC₅₀ in Molar concentration. The results arerepresented in Table 1 below.

TIE-2 Autophosphorylation Assay (TIE2-C)

The TIE-2 autophosphorylation assay used an ELISA method and a TIE2intracellular domain/c-fms extracellular domain (TIE2/c-fms) chimericprotein expressing mouse 3T3 cells. This assay measured theautophosphorylation level of TIE2 protein expressed in cells. The cellswere cultured in high glucose DMEM (Sigma) containing 10% serum at 37°C. in a humidified 10% CO2, 90% air incubator. The test compound(diluted from a 10 mM stock in DMSO, final DMSO concentration was 0.1%)was incubated with TIE2/c-fms expressing cells for 1 hr in serum freeDMEM in 96 well plates followed by the activation of TIE2/c-fms receptorusing c-fms ligand, MCSF (macrophage colony stimulating factor). Theculture media was removed by aspiration and the cells incubated for atleast 30 mins on ice with lysis buffer containing 137 mM NaCl, 2 mMEDTA, 10% glycerol, 0.09 ml sodium ortho vanadate and complete proteaseinhibitor cocktail (Roche) in 20 mM Tris-HCl (pH 8.0). The cell extractswere transferred into Rat anti-c-fms antibody coated 96 well plates andincubated for 12 hrs at 4 degrees. The extracts were removed byaspiration and the plate was incubated with biotinylatedanti-phosphotyrosine antibody, PT66 (Sigma) and then with HRP(Horseradish Peroxidase)-labeled streptavidin (PIERCE). The opticaldensity at 450 nm derived from HRP catalyzed TMB was measured with anARVO multilabel counter. (Wallac Berthold Japan). The percent inhibitionof activity was calculated relative to blank control wells. Theconcentration of test compound that inhibits 50% of activity (IC₅₀) wasinterpolated using nonlinear regression (Levernberg-Marquardt) and theequation, y=Vmax (1−x/(K+x))+Y2, where “K” was equal to the IC₅₀. TheIC₅₀ values were converted to pIC₅₀ values, i.e., −log IC₅₀ in Molarconcentration. The results are represented in Table 1 below.

Tie2 Fluorescence Polarization Kinase Activity Assay: (TIE2-FP)

Activation of Recombinant Tie2 Activation:

Recombinant GST-Tie2 was activated by incubating the enzyme in 20 mMTris-HCl, pH 7.5, 12 mM MgCl₂, 100 mM NaCl, 20 μM sodium vanidate, 1 mMDTT and 300 μM ATP at room temperature for 2 hours. The activationmixture was then passed through a NAP-25 desalting column (PharmaciaBiotech cat no. 17-0852-02) to remove the free ATP. The activated enzymewas stored as aliquots at −80° C. in 20 mM Tris-HCl, pH 7.5 and 11 mMNaCl.

Assay Conditions:

The final assay conditions were 50 mM HEPES, pH 7.5, 5% DMSO (whenscreening compounds), 200 μM ATP, 5 mM MgCl₂, 1 mM DTT, 50 μM sodiumvanidate, 1 nM activated enzyme, and 200 μM peptide. IC₅₀'s of compoundswere measured under subsaturating ATP (200 μM) and varing concentrationsof activated Tie2 and peptide substrate (RFWKYEFWR-OH; MW 1873 Da, TFAsalt). Panvera Anti-phosphotyrosine antibody (Cat#P2840) and PTK GreenTracer (Cat#P2842) were used to detect the phosphorylated peptide.Polarization was measured on a TECAN Polarion in 138-second cycles for30 minutes at room temperature. IC₅₀'s were then determined from the %polarization using normal calculation methods. Results are indicatedbelow.

VEGF-R2 Enzyme Assay (VEGF-E)

The VEGF enzyme assay used the LANCE method (Wallac) and GST-VEGFR2,baculovirus expressed recombinant constructs of the intracellulardomains of human TIE2 tagged by GST. The method measured the ability ofthe purified enzymes to catalyse the transfer of the γ-phosphate fromATP onto tyrosine residues in a biotinylated synthetic peptide,(biotin-aminohexyl-EEEEYFELVAKKKK-NH2). This peptide phosphorylation wasdetected using the following procedure: GST-VEGFR2 was incubated for40–60 mins at room temperature with 75 uM ATP, 5 mM MgCl2, 0.1 mM DTT,0.1 mg/mL BSA and the test compound (diluted from a 10 mM stock in DMSOfor desired concentration) in 100 mM HEPES buffer. The reaction wasstopped by the addition of EDTA (final concentration 50 mM).Streptavidin linked-APC (allophycocyanin, Molecular Probe) andEuropium-labeled anti-phosphorylated tyrosine antibody (Wallac) werethen added at the final concentration of 15 nM and 1 nM, respectively.The APC signal was measured using an ARVO multilabel counter (WallacBerthold, Japan). The percent inhibition of activity was calculatedrelative to blank control wells. The concentration of test compound thatinhibits 50% of activity (IC₅₀) was interpolated using nonlinearregression (Levernberg-Marquardt) and the equation, y=Vmax(1−x/(K+x))+Y2, where “K” was equal to the IC₅₀. The IC₅₀ values wereconverted to pIC₅₀ values, i.e., −log IC₅₀ in Molar concentration. Theresults are represented in Table 1 below.

VEGF-Driven Cellular Proliferation Assay. BrdU Incorporation Assay(VEGF-C)

Human umbilical cord endothelial cells (HUVEC, Clonetics, CC2519) werepassaged in Type I collagen-coated 100-mm petridishes in EGM-MV medium(Clonetics, CC3125) at 37 C in a humidified 5% CO₂, 95% air incubator.(HUVEC passaged more than 6 times in vitro were discarded and notsubjected to assaying.) The cells were harvested using trypsin/EDTA,counted using a haemocytometer and plated at 5000 cells/well in a TypeI-collagen coated 96-well plate (Becton Dickinson, 354407) in M199medium (Gibco BRL 12340-030) containing 5% FBS (Hyclone, A 1115-L) andgentamicin (at 50 ug/ml, Gibco BRL). After incubation overnight at 37°C., the media were replaced with 100 ul of M199 serum-free mediumcontaining compounds at various concentrations with 0.6% DMSO andgentamicin. The compounds were diluted in serum-free M199 medium from 10mM stock solutions prepared in 100% DMS0. After a 30 min incubation at37° C., the cells were fed with 100 ul of serum-free M199 mediumcontaining gentamicin, 0.2% culture-grade bovine serum albumin (BSA,Sigma A1993) and 20 ng/ml of VEGF (R&tD systems, 293-VE) or 0.6 ng/ml ofbasic FGF (R&tD systems, 233-FB), and cultured at 37° C. for another 24h. The cells were pulsed with bromodeoxyuridine (BrdU at 10 uM inserum-free M199) at 37° C. for an additional 24 h. The incorporation ofBrdU into the proliferating HUVEC were analyzed using BrdU CellProliferation ELISA (Roche Molecular Biochemicals, 1647229) according tothe manufacturer's protocols. The optical density at 450 nm was measuredwith a multilabel counter (ARVO SX, Wallac). The percent inhibition ofcell growth was calculated relative to blank control wells. Theconcentration of test compound that inhibits 50% of cell growth (IC₅₀)was interpolated using nonlinear regression (Levernberg-Marquardt) andthe equation, y=Vmax (1−x/(K+x))+Y2, where “K” was equal to the IC₅₀.The IC₅₀ values were converted to pIC₅₀ values, i.e., −log IC₅₀ in Molarconcentration. The results are represented in Table 1 below.

TABLE I Ex. No TIE2-E TIE2-C VEGF-E VEGF-C 1 ++ +++ +++ − 2 ++ ++ ++ 3++ 4 +++ +++ +++ +++ 5 ++ ++ +++ + 6 ++ ++ 8 +++ +++ +++ +++ 10 ++ ++ ++− 15 + + ++ + 16 + + ++ + 19 ++ + ++ − 32 + + ++ − 34 ++ − + 36 ++ + ++42 + + ++ 43 − − ++ 55 ++ ++ ++ − 57 − +++ − 72 ++ ++ 93 ++ ++ ++ − 95++ ++ ++ − 105 + ++ + + 108 ++ ++ + 131 ++ ++ ++ + 132 + ++ ++ + 135 ++++ +++ − 144 + ++ +++ − 145 ++ ++ +++ − 147 + ++ ++ + 153 ++ ++ + 159 ++++ ++ ++ 160 ++ ++ +++ − 162 ++ ++ ++ − 165 ++ ++ +++ + 166 ++ ++ +++ +176 ++ ++ ++ − 178 + ++ ++ + 179 ++ ++ − 182 ++ ++ +++ − 184 ++ ++ +++ +189 ++ ++ +++ + 191 ++ ++ ++ − 192 ++ ++ +++ + 194 ++ ++ − 196 ++ ++ +198 ++ ++ + 200 ++ ++ +++ + 204 ++ ++ + 206 ++ ++ +++ + 227 +++ +++ +++228 +++ ++ ++ 232 (8C) +++ +++ +++ +++ 237 ++ 250 +++ 262 ++ 322 +++ +386 +++ ++ 441 ++ +++ 443 +++ + 446 +++ + 448 +++ + + = pIC₅₀ of5.0–6.0; ++ = pIC₅₀ of 6.0–7.0; +++ = pIC₅₀ of >7.0; − = a negative orinconclusive result; blank = not tested

The compound of Example 276 was assayed using the TIE2-FP assay and gavean IC₅₀ of 0.0018 μM.

Structures of representative examples are presented in Table 2 throughTable 9 following.

TABLE 2

Example No R¹ R² A D Example 10 H NH₂

Example 19 H NH₂

Example 20 H NH₂

Example 27 H NH₂

Example 46 H NH₂

Example 47 H NH₂

Example 51 H NH₂

Example 58 H NH₂

TABLE 3

Example No R¹ R² A D Example 63 H NH₂

Example 66 H NH₂

Example 67 H NH₂

Example 70 H NH₂

Example 74 H

H Example 79 H NH₂

Example 81 H

Example 83 H NH₂

TABLE 4

Example No R¹ R² A D Example 91 H NH₂

Example 98 H NH₂

Example 101 H NH₂

Example 105 H NH₂

Example 117 H NH₂

Example 118 H NH₂

Example 148 H NH₂

Example 154 H NH₂

TABLE 5

Example No R¹ R² A D Example 163 H NH₂

Example 168 H NH₂

Example 169 H NH₂

Example 175 H NH₂

Example 180 H NH₂

Example 182 H NH₂

Example 187 H NH₂

Example 190 H NH₂

TABLE 6

Example No R¹ R² A D Example 196 H NH₂

Example 198 H NH₂

ExampIe 210 H NH₂

Example 213

NH₂

Example 215 H NH₂

Example 222

NH₂

Example 230 H NH₂

Example 231 H NH₂

TABLE 7

Example No R¹ R² A D Example 235 H NH₂

Example 237 H NH₂

H Example 238 H

H Example 240 H

H Example 243 H

H Example 248

H

H Example 263

H

H Example 273 H NH₂

TABLE 8

Example No R¹ R² A D Example 306 H NH₂

H Example 307 H NH₂

H Example 311 H NH₂

H Example 317 H NH₂

H Example 319 H NH₂

H Example 329 H NH₂

H Example 370 H NH₂

H Example 386 H NH₂

H

TABLE 9

Example No R¹ R² A D Example 429 H NH₂

H Example 440 H NH₂

H Example 446 H NH₂

H Example 453 H NH₂

H Example 455 H NH₂

H Example 457 H NH₂

H Example 468 H NH₂

H Example 470 H NH₂

H

1. A compound selected from the group consisting of: 4-Amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)thieno[2,3-d]pyrimidine; 4-Amino-3-(4-((2-chloro-5-(trifluoromethyl)phenyl)-aminocarbonylamino)phenyl)thieno[2,3-d]pyrimidine; 4-Amino-3-(4-(((S)-2-amino-2-phenylacetyl)amino)phenyl)-thieno[2,3-d]pyrimidine; 4-Amino-3-(4-(((1S,2S)-2-phenyl-cyclopropanecarbonyl)amino)-phenyl)thieno[2,3-d]pyrimidine; 4-Amino-3-(4-(((R)-2-amino-2-phenylacetyl)amino)phenyl)-thieno[2,3-d]pyrimidine; 4-Amino-3-(4-(((1R,2R)-2-phenyl-cyclopropanecarbonyl)amino)-phenyl)thieno[2,3-d]pyrimidine; 4-Amino-3-(4-((1-phenylcyclopentanecarbonyl)amino)-phenyl)thieno[2,3-d]pyrimidine; 4-Amino-3-(4-((2-phenylisobutyryl)amino)phenyl)thieno[2,3-d]pyrimidine; 4-Amino-3-(4-(((bicyclo[4.2.0]octa-1(6),2,4-trien-7-yl)carbonyl)-amino)phenyl)thieno[2,3-d]pyrimidine; 4-Amino-3-(4-((2-phenylbutyryl)amino)phenyl)thieno[2,3-d]pyrimidine; 4-Amino-3-(4-(((5-methyl-[1,3,4]thiadiazol-2-yl)carbonyl)amino)phenyl)thieno[2,3-d]pyrimidine; 4-Amino-3-(4-(((5-tert-butyl-2-methyl-2H-pyrazol-3-yl)carbonyl)amino)phenyl)thieno[2,3-d]pyrimidine; 4-Amino-3-(4-((1-(3,4-dichlorophenyl)-cyclopropanecarbonyl)amino)phenyl)thieno[2,3-d]pyrimidine; 4-Amino-3-(4-((1-(2,5-difluorophenyl)-cyclopropanecarbonyl)amino)phenyl)thieno[2,3-d]pyrimidine; 4-Amino-3-(4-((1-(3,5-bis-(trifluoromethyl)phenyl)-cyclopropanecarbonyl)amino)phenyl)thieno[2,3-d]pyrimidine; 4-Amino-3-(4-((1-(3-chlorophenyl)cyclopropanecarbonyl)amino)-phenyl)thieno[2,3-d]pyrimidine; and 4-Amino-3-(4-((1-(3-(trifluoromethyl)phenyl)-cyclopropanecarbonyl)amino)phenyl)thieno[2,3-d]pyrimidine; or a salt thereof.
 2. A pharmaceutical composition, comprising a therapeutically effective amount of a compound as claimed in claim 1, or a salt thereof and one or more of pharmaceutically acceptable carriers, diluents and excipients. 